Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration

ABSTRACT

Methods of treating a heart condition include administering by inhalation an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof. Nebulized drug product and kits are also contemplated.

CROSS-REFERENCE

This application is a continuation of U.S. patent application Ser. No.16/192,337, filed Nov. 15, 2018, which is a continuation of PCTApplication No. PCT/US2018/032092, filed May 10, 2018, which claims thebenefit of U.S. Provisional Application No. 62/504,292, filed May 10,2017, each of which is incorporated herein by reference in its entirety.

BACKGROUND 1. Field of the Invention

The present invention relates to compositions, unit doses, aerosols, andkits for treating certain heart conditions by pulmonary administrationand methods thereof.

2. Background Art

Cardiac arrhythmia (also dysrhythmia) is a term for any of a large andheterogeneous group of conditions in which there is abnormal electricalactivity in the heart. The heart beat may be too fast or too slow, andmay be regular or irregular.

Atrial arrhythmia therapy is a field with a high level of unmet clinicalneed. Many drugs used today have been on the market since the early1980s and 1990s and are mostly inadequate due to either lack of efficacyor a side-effect profile that is often cardiac related, thatnecessitates extensive monitoring of the patient.

What is needed for fast and safe cardioversion (resolution ofarrhythmia) is therapy that:

(a) has little to no risk of acceleration of ventricular rate beforecardioversion;

(b) slows atrio-ventribular (AV) conduction so that there is ventricularrate control and cardioversion at the same time;

(c) has minimal to no effect in prolonging the QRS interval above theupper range of normal value (about 120 milliseconds) and should have alow risk of torsade de pointes; and

(d) has minimal to no negative inotropic effect; it should have onlymild negative chronotropic effect, without the risk of severebradycardia when the patient reverts to sinus rhythm.

None of the current approved drug products exhibit thesecharacteristics. High oral and intravenous (IV) doses required tocompensate for absorption, metabolism, and dilution result in blood highblood concentrations for an extended period of time that can cause thedangerous adverse cardiac events like pro-arrhythmias, QT prolongation,and torsade de pointes. FELDMAN et al., “Analysis of Coronary Responseto Various Doses of Intracoronary Nitroglycerin,” Circulation,66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in HumanAtherosclerotic Coronary Arteries,” Circulation, 111:288-294 (2005).Comorbid conditions also limit use of ideal drugs in some patients, forexample the case with intravenous adenosine. GAGLIONE et al., “Is ThereCoronary Vasoconstriction after Intracoronary Beta-adrenergic Blockadein Patients with Coronary Artery Disease,” J Am Coll Cardiol, 10:299-310(1987). Drugs like verapamil and diltiazem injections are second line oftherapy requiring close monitoring of patients. NOGUCHI et al., “Effectsof Intracoronary Propranolol on Coronary Blood Flow and RegionalMyocardial Function in Dogs,” Eur J Pharmacol., 144(2):201-10 (1987);and ZALEWSKI et al., “Myocardial Protection during Transient CoronaryArtery Occlusion in Man: Beneficial Effects of Regional Beta-adrenergicBlockade,” Circulation, 73:734-73 (1986).

Paroxysmal atrial fibrillation (PAF) is a subset of the overall atrialfibrillation (AF) population and is estimated to be 25-30% of theoverall AF population. About 2.5 million patients are affected by AF inthe United States. The population of PAF patients is estimated to be900,000 to 1.5 million worldwide.

Paroxysmal supraventricular tachycardia (PSVT) is a type of arrhythmiathat affects about 500,000 to 600,000 patients in the United States.

Ablation techniques, e.g., RF ablation, are often used to treatarrhythmias. But ablation is expensive with the cost typically rangingfrom about $25,000 to $36,000 per procedure. Despite the high expense,ablation may not completely correct the arrhythmia. Often, multipleablation procedures are required to achieve a satisfactory therapeuticresult.

Oral medications, e.g., pills, tend to require high doses and long timefor onset of action. The oral dose for heart medications generally tendsto be well over 1 mg. High doses increase the likelihood of side effectsand drug-drug interactions as these patients typically take multiplemedications. The time for onset for oral cardiovascular medicationstends to be around 60 minutes. Oral antiarrhythmic medications have beenpredominantly developed for prevention whereas treatment being givenintravenously.

Intravenous injection usually requires a hospital setting foradministering a medicine and typically involves a visit to the emergencyroom (ER). These overheads result in this therapy being expensivecompared to therapies where the patients can self-administer theirmedicines. Intravenous injection requires a dose that is higher thanwhat is actually needed in the heart to compensate for dilution andmetabolism. Drug injected by IV passes through the right side of theheart and then the lungs before reaching the left side of the heart. SeeFIG. 1 . The drug remains in the blood stream at a high concentrationbathing all the organs and tissues with this drug in a highconcentration, until the drug gets excreted through the kidneys orthrough other metabolic routes (e.g., hepatic). As a result, IV drugsmay cause unwanted side effects. Drugs administered via the IV route aresignificantly diluted in the venous blood volume and lungs beforereaching the cardiac circulation.

Injecting a drug to the heart directly is usually a last-resort taken bya cardiologist as a life saving measure in an emergency. The doses ofthe drugs injected directly into the heart in this manner are usuallyless than their IV and/or oral doses.

In some cases, an unplanned surgery is necessary to save the patient'slife. Of course, unplanned surgeries are expensive and risky to thepatient.

Cardiac arrhythmias are associated with disabling symptoms liketightness around the chest, palpitations, feeling tired, shortness ofbreath, and sometimes chest pain.

In view of the above, arrhythmias frequently result in emergency room(ER) visits, where intravenous drugs are administered, sometimesnecessitating an extended stay in the hospital and in some cases alsoleading to unplanned invasive procedures. Pipeline Insights:Antiarrhythmics, Datamonitor (June 2006); and TWISS et al., “Efficacy ofCalcium Channel Blockers as Maintenance Therapy for Asthma,” British Jof Clinical Pharmacology (November 2001).

There remains, however, a need for improved compositions and methods fortreating heart conditions. Accordingly, there also remains a need formethods of making these compositions.

SUMMARY

Accordingly, the present invention provides compositions, unit doses,aerosols, kits, and methods for treating certain heart conditions. Otherfeatures and advantages of the present invention will be set forth inthe description of invention that follows, and in part will be apparentfrom the description or may be learned by practice of the invention. Theinvention will be realized and attained by the compositions and methodsparticularly pointed out in the written description and claims hereof.

A first embodiment of the present invention is directed to a method oftreating atrial arrhythmia. The method comprises administering aneffective amount of at least one antiarrhythmic pharmaceutical agent toa patient in need thereof, such that the at least one antiarrhythmicpharmaceutical agent first enters the heart through the pulmonary veinto the left atrium.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, e.g., tachycardia. The method comprisesadministering by inhalation (e.g., oral inhalation) an effective amountof at least one antiarrhythmic pharmaceutical agent to a patient in needthereof, wherein an amount of the at least one antiarrhythmicpharmaceutical agent peaks in the coronary circulation of the heart at atime ranging from 10 seconds to 30 minutes from administration (e.g.,initiation of the administration or end of the administration). In somecases, coronary circulation can be a coronary artery or a coronary vein,including coronary sinus.

In yet another aspect, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia. The method comprisesself-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate. The methodalso comprises self-administering by inhalation (e.g., oral inhalation)an effective amount of at least one antiarrhythmic pharmaceutical agentwithin two hours, one hour, 30 minutes, or 15 minutes of theself-diagnosing.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an electrophysiologic effect is observed, viaelectrocardiography, at a time ranging from 10 seconds to 30 minutesfrom the administration.

In still another aspect, the present invention is directed to a methodof treating atrial arrhythmia, comprising administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a cardiac score from a monitor implementing an arrhythmiadetection algorithm shows a transition from an arrhythmic state tonormal sinus rhythm in the patient at a time ranging from 10 seconds to30 minutes from the administration.

In yet another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a short form-36 quality of life score of the patient improves ata time ranging from 10 seconds to 30 minutes from the administration.

In another aspect, the present invention is directed to a unit dosecomprising a unit dose receptacle and a composition within the unit dosereceptacle. The composition comprises at least one antiarrhythmicpharmaceutical agent in an amount less than or equal to an amount of thesame at least one antiarrhythmic pharmaceutical agent administeredintravenously in the arm to achieve a minimum effective amount in thecoronary circulation, and a pharmaceutically acceptable excipient.

In still another aspect, the present invention is directed to an aerosolcomprising particles having a mass median aerodynamic diameter less than10 μm. The particles comprise at least one antiarrhythmic pharmaceuticalagent in an amount less than or equal to an amount of the same at leastone antiarrhythmic pharmaceutical agent administered intravenously inthe arm to achieve a minimum effective amount in the coronarycirculation, and a pharmaceutically acceptable excipient.

Yet another aspect of the present invention is directed to a kit. Thekit comprises a container containing at least one antiarrhythmicpharmaceutical agent and an aerosolization device.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering an effectiveamount of at least one antiarrhythmic pharmaceutical agent to a patientin need thereof, such that the at least one antiarrhythmicpharmaceutical agent first enters the heart through the pulmonary veinto the left atrium. In some cases, an amount of the at least oneantiarrhythmic pharmaceutical agent peaks in the coronary circulation ofthe heart at a time ranging from 10 seconds to 30 minutes from theadministration. In some cases, the amount of the at least oneantiarrhythmic pharmaceutical agent in the coronary circulation of theheart peaks at a time ranging from 2 minutes to 8 minutes from theadministration. In some cases, the amount of the at least oneantiarrhythmic pharmaceutical agent in the coronary circulation of theheart ranges from 0.1 mg/L to 60 mg/L at 2.5 minutes after theadministration. In some cases, the amount of the at least oneantiarrhythmic pharmaceutical agent in the coronary circulation of theheart is less than 0.1 mg/L at 30 minutes after the administration. Insome cases, the effective amount is an effective amount for only onepass through the heart. In some cases, 10% to 60% of the nominal dose ofthe administered at least one antiarrhythmic pharmaceutical agentreaches the coronary circulation. In some cases, an amount ofadministered antiarrhythmic pharmaceutical agent entering the patientranges from 0.1 mg to 200 mg. In some cases, a nominal amount of the atleast one antiarrhythmic pharmaceutical agent administered viainhalation (e.g., oral inhalation) is less than or equal to an amount ofthe same antiarrhythmic pharmaceutical agent administered intravenouslyin the arm to achieve the same amount in the coronary circulation. Insome cases, the administering comprises 1 to 6 inhalations.

In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one member selected from class Ia, class Ib, classIc, class II, class III, class IV, and class V antiarrhythmics. In somecases, the at least one antiarrhythmic pharmaceutical agent comprises atleast one class Ia antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Iaantiarrhythmic selected from quinidine, procainamide, and disopyramide.In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one class Ib antiarrhythmic. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass Ib antiarrhythmic selected from lidocaine, tocainide, phenytoin,moricizine, and mexiletine. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Icantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class Ic antiarrhythmicselected from flecainide, propafenone, and moricizine. In some cases,the at least one antiarrhythmic pharmaceutical agent comprises at leastone class II antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIantiarrhythmic selected from propranolol, acebutolol, soltalol, esmolol,timolol, metoprolol, and atenolol. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIIantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class III antiarrhythmicselected from amiodarone, sotalol, bretylium, ibutilide,methanesulfonamide, vernakalant, and dofetilide. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass IV antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class IV antiarrhythmicselected from bepridil, nitrendipine, amlodipine, isradipine,nifedipine, nicardipine, verapamil, and diltiazem. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass V antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class V antiarrhythmicselected from digoxin and adenosine.

In some cases, the atrial arrhythmia comprises tachycardia. In somecases, the atrial arrhythmia comprises supraventricular tachycardia. Insome cases, the atrial arrhythmia comprises paroxysmal supraventriculartachycardia. In some cases, the atrial arrhythmia comprises atrialfibrillation. In some cases, the atrial arrhythmia comprises paroxysmalatrial fibrillation. In some cases, the atrial arrhythmia comprises ofacute episodes in persistent and permanent atrial fibrillation. In somecases, the atrial arrhythmia comprises atrial flutter. In some cases,the atrial arrhythmia comprises paroxysmal atrial flutter. In somecases, the atrial arrhythmia comprises lone atrial fibrillation. In somecases, the administering comprises administering a liquid comprising theat least one antiarrhythmic pharmaceutical agent. In some cases, theadministering comprises administering a powder comprising the at leastone antiarrhythmic pharmaceutical agent. In some cases, theadministering comprises administering a condensation aerosol comprisingthe at least one antiarrhythmic pharmaceutical agent. In some cases, theadministering comprises administering a composition compnslng the atleast one antiarrhythmic pharmaceutical agent, wherein the compositionis not a condensation aerosol.

In some cases, the pulmonary administration comprises nebulizing asolution comprising the at least one antiarrhythmic pharmaceuticalagent. In some cases, the nebulizing comprises nebulizing with avibrating mesh nebulizer. In some cases, the nebulizing comprisesnebulizing with a jet nebulizer. In some cases, the nebulizing comprisesnebulizing with a breach-activated nebulizer. In some cases, thenebulizing comprises forming droplets having a mass median aerodynamicdiameter of less than 10 μm. In some cases, the pulmonary administrationcomprises administering a dry powder comprising the at least oneantiarrhythmic pharmaceutical agent. In some cases, the dry powdercomprises particles having a mass median aerodynamic diameter of lessthan 10 μm. In some cases, the dry powder is administered via an activedry powder inhaler. In some cases, the dry powder is administered via apassive dry powder inhaler. In some cases, the pulmonary administrationcomprises administering the at least one antiarrhythmic pharmaceuticalagent via a metered dose inhaler. In some cases, the metered doseinhaler forms particles having a mass median aerodynamic diameter ofless than 10 μm. In some cases, the metered dose inhaler contains the atleast one antiarrhythmic pharmaceutical agent formulated in a carrierselected from hydrofluoroalkane and chlorofluorocarbon. In some cases,the treating comprises acute treatment after detection of atrialarrhythmia. In some cases, the patient has normal sinus rhythm within 10minutes of initiating the administering.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an amount of the at least one antiarrhythmic pharmaceuticalagent peaks in the coronary circulation of the heart at a time rangingfrom 10 seconds to 30 minutes from the administration. In some cases,the amount of the at least one antiarrhythmic pharmaceutical agent inthe coronary circulation of the heart peaks at a time ranging from 2minutes to 8 minutes from the administration. In some cases, the amountof the at least one antiarrhythmic pharmaceutical agent in the coronarycirculation of the heart ranges from 0.1 mg/L to 60 mg/L at 2.5 minutesafter the administration. In some cases, the amount of the at least oneantiarrhythmic pharmaceutical agent in the coronary circulation of theheart is less than 0.1 mg/L at 30 minutes after the administration. Insome cases, the effective amount is an effective amount for only onepass through the heart. In some cases, 10% to 60% of the nominal dose ofthe administered at least one antiarrhythmic pharmaceutical agentreaches the coronary circulation. In some cases, an amount ofadministered antiarrhythmic pharmaceutical agent entering the patientranges from 0.1 mg to 200 mg. In some cases, a nominal amount of the atleast one antiarrhythmic pharmaceutical agent administered viainhalation (e.g., oral inhalation) is less than or equal to an amount ofthe same antiarrhythmic pharmaceutical agent administered intravenouslyin the arm to achieve the same amount in the coronary circulation. Insome cases, the administering comprises 1 to 6 inhalations.

In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one member selected from class Ia, class Ib, classIc, class II, class III, class IV, and class V antiarrhythmics. In somecases, the at least one antiarrhythmic pharmaceutical agent comprises atleast one class Ia antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Iaantiarrhythmic selected from quinidine, procainamide, and disopyramide.In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one class Ib antiarrhythmic. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass Ib antiarrhythmic selected from lidocaine, tocainide, phenytoin,moricizine, and mexiletine. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Icantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class Ic antiarrhythmicselected from flecainide, propafenone, and moricizine. In some cases,the at least one antiarrhythmic pharmaceutical agent comprises at leastone class II antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIantiarrhythmic selected from propranolol, acebutolol, soltalol, esmolol,timolol, metoprolol, and atenolol. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIIantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class III antiarrhythmicselected from amiodarone, sotalol, bretylium, ibutilide,methanesulfonamide, vernakalant, and dofetilide. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass IV antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class IV antiarrhythmicselected from bepridil, nitrendipine, amlodipine, isradipine,nifedipine, nicardipine, verapamil, and diltiazem. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass V antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class V antiarrhythmicselected from digoxin and adenosine.

In some cases, the atrial arrhythmia comprises tachycardia. In somecases, the atrial arrhythmia comprises supraventricular tachycardia. Insome cases, the atrial arrhythmia comprises paroxysmal supraventriculartachycardia. In some cases, the atrial arrhythmia comprises atrialfibrillation. In some cases, the atrial arrhythmia comprises paroxysmalatrial fibrillation. In some cases, the atrial arrhythmia comprises ofacute episodes in persistent and permanent atrial fibrillation. In somecases, the atrial arrhythmia comprises atrial flutter. In some cases,the atrial arrhythmia comprises paroxysmal atrial flutter. In somecases, the atrial arrhythmia comprises lone atrial fibrillation.

In some cases, the administering comprises administering a liquidcomprising the at least one antiarrhythmic pharmaceutical agent. In somecases, the administering comprises administering a powder comprising theat least one antiarrhythmic pharmaceutical agent. In some cases, theadministering comprises administering a condensation aerosol comprisingthe at least one antiarrhythmic pharmaceutical agent. In some cases, theadministering comprises administering a composition comprising the atleast one antiarrhythmic pharmaceutical agent, wherein the compositionis not a condensation aerosol. In some cases, the pulmonaryadministration comprises nebulizing a solution comprising the at leastone antiarrhythmic pharmaceutical agent. In some cases, the nebulizingcomprises nebulizing with a vibrating mesh nebulizer. In some cases, thenebulizing comprises nebulizing with a jet nebulizer. In some cases, thenebulizing comprises forming droplets having a mass median aerodynamicdiameter of less than 10 μm. In some cases, the pulmonary administrationcomprises administering a dry powder comprising the at least oneantiarrhythmic pharmaceutical agent. In some cases, the dry powdercomprises particles having a mass median aerodynamic diameter of lessthan 10 μm. In some cases, the dry powder is administered via an activedry powder inhaler. In some cases, the dry powder is administered via apassive dry powder inhaler. In some cases, the pulmonary administrationcomprises administering the at least one antiarrhythmic pharmaceuticalagent via a metered dose inhaler. In some cases, the metered doseinhaler forms particles having a mass median aerodynamic diameter ofless than 10 μm. In some cases, the metered dose inhaler contains the atleast one antiarrhythmic pharmaceutical agent formulated in a carrierselected from hydrofluroalkane and chloroflurocarbon.

In some cases, the treating comprises acute treatment after detection ofatrial arrhythmia. In some cases, the patient has normal sinus rhythmwithin 30 minutes of initiating the administration. In some cases, thepatient has normal sinus rhythm within 10 minutes of initiating theadministration.

In another aspect, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia, comprising:self-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate; andself-administering by inhalation (e.g., oral inhalation) an effectiveamount of at least one antiarrhythmic pharmaceutical agent within twohours of the self-diagnosing. In some cases, the self-administeringoccurs within one hour of the self-diagnosing. In some cases, theself-administering occurs within 30 minutes of the self-diagnosing. Insome cases, the self-administering occurs within 15 minutes of theself-diagnosing. In some cases, the self-administering continues untilthe patient no longer detects the at least one of shortness of breath,heart palpitations, and above normal heart rate.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an electrophysiologic effect is observed, viaelectrocardiography, at a time ranging from 10 seconds to 30 minutesfrom the administration. In some cases, the electrophysiologic effectcomprises a transition from arrhythmia to a normal sinus rhythm. In somecases, the electro physiologic effect comprises a transition from anabsence of a P wave to a presence of a P wave.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a cardiac score from a monitor implementing an arrhythmiadetection algorithm shows a transition from an arrhythmic state tonormal sinus rhythm in the patient at a time ranging from 10 seconds to30 minutes from the administration. In some cases, the monitor comprisesa Holter monitor, telemetry, and mobile ECG.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering by inhalation(e.g., oral inhalation) an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a short form-36 quality of life score of the patient improves ata time ranging from 10 seconds to 30 minutes from the administration.

In another aspect, the present invention is directed to a unit dosecomprising: a unit dose receptacle; a composition within the unit dosereceptacle, the composition comprising: at least one antiarrhythmicpharmaceutical agent in an amount less than or equal to an amount of thesame at least one antiarrhythmic pharmaceutical agent administeredintravenously in the arm to achieve a minimum effective amount in thecoronary circulation; and a pharmaceutically acceptable excipient. Insome cases, the composition comprises a solution. In some cases, thecomposition comprises a solution having a tonicity that ranges fromisotonic to physiologic isotonicity. In some cases, the compositioncomprises an aqueous solution. In some cases, the composition comprisesa non-aqueous solution. In some cases, the composition further comprisesa pH buffer. In some cases, the composition further comprises a pHbuffer selected from citrate, phosphate, phthalate, and lactate. In somecases, the composition consists essentially of the at least oneantiarrhythmic pharmaceutical agent and water. In some cases, thecomposition consists essentially of the at least one antiarrhythmicpharmaceutical agent, water, and a pH buffer. In some cases, thecomposition has a pH ranging from 3.5 to 8.0.

In some cases, the pharmaceutically acceptable excipient compriseshydrofluoroalkane. In some cases, the pharmaceutically acceptableexcipient comprises chlorofluoralkane. In some cases, the composition issubstantially preservative-free. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one memberselected from class Ia, class Ib, class Ic, class II, class III, classIV, and class V antiarrhythmics. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Iaantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class Ia antiarrhythmicselected from quinidine, procainamide, and disopyramide, andpharmaceutically acceptable salts thereof. In some cases, the at leastone antiarrhythmic pharmaceutical agent comprises at least one class Ibantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class Ib antiarrhythmicselected from lidocaine, tocainide, phenytoin, moricizine, andmexiletine, and pharmaceutically acceptable salts thereof. In somecases, the at least one antiarrhythmic pharmaceutical agent comprises atleast one class Ic antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Icantiarrhythmic selected from flecainide, propafenone, and moricizine,and pharmaceutically acceptable salts thereof. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass II antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class II antiarrhythmicselected from propranolol, acebutolol, soltalol, esmolol, timolol,metoprolol, and atenolol, and pharmaceutically acceptable salts thereof.In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one class III antiarrhythmic. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass III antiarrhythmic selected from amiodarone, sotalol, bretylium,ibutilide, methanesulfonamide, vernakalant, and dofetilide, andpharmaceutically acceptable salts thereof. In some cases, the at leastone antiarrhythmic pharmaceutical agent comprises at least one class IVantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class IV antiarrhythmicselected from bepridil, nimodipine, nisoldipine, nitrendipine,amlodipine, isradipine, nifedipine, nicardipine, verapamil, anddiltiazem, and pharmaceutically acceptable salts thereof. In some cases,the at least one antiarrhythmic pharmaceutical agent comprises at leastone class V antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Vantiarrhythmic selected from digoxin and adenosine, and pharmaceuticallyacceptable salts thereof. In some cases, the receptacle comprises 0.1 mgto 200 mg of the at least one antiarrhythmic pharmaceutical agent. Insome cases, the unit dose is substantially tasteless.

In another aspect, the present invention is directed to an aerosolcomprising particles having a mass median aerodynamic diameter less than10 μm, wherein the particles comprise: at least one antiarrhythmicpharmaceutical agent in an amount less than or equal to an amount of thesame at least one antiarrhythmic pharmaceutical agent administeredintravenously in the arm to achieve a minimum effective amount in thecoronary circulation; and a pharmaceutically acceptable excipient.

In some cases, the particles comprise a nebulized solution. In somecases, the particles comprise a nebulized aqueous solution. In somecases, the particles further comprise a pH buffer. In some cases, theparticles further comprise a pH buffer selected from citrate, phosphate,phthalate, and lactate. In some cases, the particles consist essentiallyof the at least one antiarrhythmic pharmaceutical agent and water. Insome cases, the particles consist essentially of the at least oneantiarrhythmic pharmaceutical agent, water, and a pH buffer. In somecases, the particles have a pH ranging from 3.5 to 8.0. In some cases,the particles are substantially preservative-free.

In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one member selected from class Ia, class Ib, classIc, class II, class III, class IV, and class V antiarrhythmics. In somecases, the at least one antiarrhythmic pharmaceutical agent comprises atleast one class Ia antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Iaantiarrhythmic selected from quinidine, procainamide, and disopyramide.In some cases, the at least one antiarrhythmic pharmaceutical agentcomprises at least one class Ib antiarrhythmic. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass Ib antiarrhythmic selected from lidocaine, tocainide, phenytoin,moricizine, and mexiletine. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class Icantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class Ic antiarrhythmicselected from flecainide, propafenone, and moricizine. In some cases,the at least one antiarrhythmic pharmaceutical agent comprises at leastone class II antiarrhythmic. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIantiarrhythmic selected from propranolol, acebutolol, soltalol, esmolol,timolol, metoprolol, and atenolol. In some cases, the at least oneantiarrhythmic pharmaceutical agent comprises at least one class IIIantiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class III antiarrhythmicselected from amiodarone, sotalol, bretylium, ibutilide,methanesulfonamide, vernakalant, and dofetilide. In some cases, the atleast one antiarrhythmic pharmaceutical agent comprises at least oneclass IV antiarrhythmic. In some cases, the at least one antiarrhythmicpharmaceutical agent comprises at least one class IV antiarrhythmicselected from bepridil, nimodipine, nisoldipine, nitrendipine,amlodipine, isradipine, nifedipine, nicardipine, verapamil, anddiltiazem. In some cases, the at least one antiarrhythmic pharmaceuticalagent comprises at least one class V antiarrhythmic. In some cases, theat least one antiarrhythmic pharmaceutical agent comprises at least oneclass V antiarrhythmic selected from digoxin and adenosine. In somecases, the aerosol is substantially tasteless.

In another aspect, the present invention is directed to a kit,comprising: a container containing at least one antiarrhythmicpharmaceutical agent; and an aerosolization device. In some cases, theaerosolization device comprises a nebulizer. In some cases, theaerosolization device comprises a vibrating mesh nebulizer. In somecases, the aerosolization device comprises a jet nebulizer. In somecases, the aerosolization device comprises a dry powder inhaler. In somecases, the aerosolization device comprises an active dry powder inhaler.In some cases, the aerosolization device comprises a passive dry powderinhaler. In some cases, the aerosolization device comprises a metereddose inhaler. In some cases, an amount of the at least oneantiarrhythmic pharmaceutical agent is sufficient to produce anelectrophysiologic effect with a minimum of one pass through the heart.In some cases, the effective amount of the at least one antiarrhythmicpharmaceutical agent is sub-therapeutic when diluted by overall bloodvolume.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering to one or morepulmonary veins through pulmonary airways and through use of anaerosolization device an effective amount of at least one antiarrhythmicpharmaceutical agent selected from a group consisting of class I, classII, class III, and class IV antiarrhythmics, to a patient in needthereof, wherein the effective amount of the at least one antiarrhythmicpharmaceutical agent is a total amount from 0.1 mg to 200 mgadministered over multiple inhalations, wherein the at least oneantiarrhythmic pharmaceutical agent level peaks in a coronarycirculation of the heart at a time between 30 seconds and 20 minutesfrom the pulmonary administration, and wherein the patient's sinusrhythm is restored to normal within 30 minutes of initiating theadministration.

In some cases, the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart rangesbetween 0.1 mg/L and 60 mg/L at 2.5 minutes after pulmonaryadministration, and the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart is lessthan 0.1 mg/L at 30 minutes after pulmonary administration, or wherein10% to 60% of a nominal dose of the administered at least oneantiarrhythmic pharmaceutical agent reaches the coronary circulation. Insome cases, the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart is between0.1 mg/L and 20 mg/L at 2.5 minutes after pulmonary administration, andthe concentration of the at least one antiarrhythmic pharmaceuticalagent in the coronary circulation of the heart is less than 0.1 mg/L at30 minutes after pulmonary administration, or wherein between 5% and 60%of a nominal dose of the administered at least one antiarrhythmicpharmaceutical agent reaches the coronary circulation. In some cases,the method comprises pulmonary administration of the at least oneantiarrhythmic in up to 6 inhalations. In some cases, the atrialarrhythmia comprises tachycardia. In some cases, the tachycardiacomprises supraventricular tachycardia, paroxysmal supraventriculartachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acuteepisodes in persistent and permanent atrial fibrillation, atrialflutter, paroxysmal atrial flutter or lone atrial fibrillation. In somecases, the method comprises administering a liquid, dry powder, ornebulized droplets comprising the at least one antiarrhythmicpharmaceutical agent, wherein the powder or nebulized droplets have amass median aerodynamic diameter of less than 10 μm.

In some cases, the antiarrhythmic pharmaceutical agent is a class Iantiarrhythmic. In some cases, the class I antiarrhythmic is a class Ia,Ib, or Ic antiarrhythmic. In some cases, the antiarrhythmicpharmaceutical agent is a class II antiarrhythmic. In some cases, theclass II antiarrhythmic is esmolol HCl. In some cases, dosage of theesmolol HCl is between 0.5 and 0.75 mg/kg body weight. In some cases,the antiarrhythmic pharmaceutical agent is a class IV antiarrhythmic. Insome cases, the class IV antiarrhythmic is diltiazem. In some cases,dosage of the diltiazem is 0.25 mg/kg body weight. In some cases, the atleast one antiarrhythmic pharmaceutical agent level peaks in thecoronary circulation of the heart at a time between 1 minute and 10minutes. In some cases, the aerosolization device is a nebulizerconfigured to administer the at least one antiarrhythmic pharmaceuticalagent in a liquid pharmaceutical formulation, wherein the aerosolizationoccurs at room temperature. In some cases, the at least oneantiarrhythmic pharmaceutical agent is self-administered by the patient.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering to one or morepulmonary veins through pulmonary airways and through use of anaerosolization device an effective amount of at least one antiarrhythmicpharmaceutical agent selected from a group consisting of class I, classII, class III, and class IV antiarrhythmics, to a patient in needthereof, wherein the patient self-administers and self-titrates aneffective inhaled dose of at least one antiarrhythmic pharmaceuticalagent for a conversion of atrial arrhythmia to normal sinus rhythm,wherein the at least one antiarrhythmic pharmaceutical agent level peaksin a coronary circulation of the heart at a time between 30 seconds and20 minutes from the pulmonary administration, and wherein the patient'ssinus rhythm is restored to normal within 30 minutes of initiating theadministration.

In some cases, the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart rangesbetween 0.1 mg/L and 60 mg/L at 2.5 minutes after pulmonaryadministration, and the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart is lessthan 0.1 mg/L at 30 minutes after pulmonary administration, or wherein10% to 60% of the nominal dose of the administered at least oneantiarrhythmic pharmaceutical agent reaches the coronary circulation.

In some cases, the concentration of the at least one antiarrhythmicpharmaceutical agent in the coronary circulation of the heart is between0.1 mg/L and 20 mg/L at 2.5 minutes after pulmonary administration, andthe concentration of the at least one antiarrhythmic pharmaceuticalagent in the coronary circulation of the heart is less than 0.1 mg/L at30 minutes after pulmonary administration, or wherein between 5% and 60%of the nominal dose of the administered at least one antiarrhythmicpharmaceutical agent reaches the coronary circulation. In some cases,the method comprises pulmonary administration of the at least oneantiarrhythmic in up to 6 inhalations.

In some cases, the atrial arrhythmia comprises tachycardia. In somecases, the tachycardia comprises supraventricular tachycardia,paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmalatrial fibrillation, acute episodes in persistent and permanent atrialfibrillation, atrial flutter, paroxysmal atrial flutter or lone atrialfibrillation. In some cases, the method comprises administering aliquid, dry powder, or nebulized droplets comprising the at least oneantiarrhythmic pharmaceutical agent, wherein the dry powder or nebulizeddroplets have a mass median aerodynamic diameter of less than 10 μm.

In some cases, the antiarrhythmic pharmaceutical agent is a class Iantiarrhythmic. In some cases, the class I antiarrhythmic is a class Ia,Ib, or Ic antiarrhythmic. In some cases, the antiarrhythmicpharmaceutical agent is a class II antiarrhythmic. In some cases, theclass II antiarrhythmic is esmolol HCl. In some cases, the effectiveinhaled dose of the esmolol HCl is between 0.5 and 0.75 mg/kg bodyweight. In some cases, the antiarrhythmic pharmaceutical agent is aclass IV antiarrhythmic. In some cases, the class IV antiarrhythmic isdiltiazem. In some cases, the effective inhaled dose of the diltiazem is0.25 mg/kg body weight. In some cases, the at least one antiarrhythmicpharmaceutical agent level peaks in the coronary circulation of theheart at a time between 1 minute and 10 minutes. In some cases, theaerosolization device is a nebulizer configured to administer the atleast one antiarrhythmic pharmaceutical agent in a liquid pharmaceuticalformulation, wherein the aerosolization occurs at room temperature.

In another aspect, the present invention is directed to a method oftreating atrial arrhythmia, comprising: administering to one or morepulmonary veins through pulmonary airways by inhalation (e.g., oralinhalation) an effective amount of at least one antiarrhythmicpharmaceutical agent selected from a group consisting of class I, classII, class III, and class IV antiarrhythmics, to a subject in needthereof, wherein the effective amount of the at least one antiarrhythmicpharmaceutical agent is a total amount from 0.1 mg to 200 mg and has: i)a T_(max) of from about 0.1 minute to about 30 minutes; ii) a C_(max) offrom about 10 ng/mL to about 5000 ng/mL; iii) an AUC_(Last) of fromabout 100 hr*ng/mL to about 10000 hr*ng/mL; iv) a distribution t_(1/2)of from about 0.1 minute to about 15 minutes; v) an elimination t_(1/2)of from about 1 hour to about 25 hours; vi) a ΔQRS of from about 0.01msec to about 100 msec; or any combination thereof.

In some cases, the at least one antiarrhythmic pharmaceutical agent isadministered over multiple inhalations. In some cases, the at least oneantiarrhythmic pharmaceutical agent is administered in up to 6inhalations. In some cases, the subject's sinus rhythm is restored tonormal within 30 minutes of initiating the administration. In somecases, the at least one antiarrhythmic pharmaceutical agent level peaksin a coronary circulation of the heart at a time between 30 seconds and20 minutes from the administration. In some cases, concentration of theat least one antiarrhythmic pharmaceutical agent in the coronarycirculation of the heart ranges between 0.1 mg/L and 60 mg/L at 2.5minutes after the administration. In some cases, concentration of the atleast one antiarrhythmic pharmaceutical agent in the coronarycirculation of the heart is less than 0.1 mg/L at 30 minutes after theadministration. In some cases, 5% to 60% of a nominal dose of theadministered at least one antiarrhythmic pharmaceutical agent reachesthe coronary circulation. In some cases, the effective amount of the atleast one antiarrhythmic pharmaceutical agent has a T_(max) of fromabout 0.1 minute to about 30 minutes. In some cases, the effectiveamount of the at least one antiarrhythmic pharmaceutical agent has aT_(max) of from about 1 minute to about 5 minutes. In some cases, theeffective amount of the at least one antiarrhythmic pharmaceutical agenthas a T_(max) of from about 0.1 minute to about 3 minutes. In somecases, the effective amount of the at least one antiarrhythmicpharmaceutical agent has a T_(max) of from about 0.2 minute to about 5minutes. In some cases, the effective amount of the at least oneantiarrhythmic pharmaceutical agent has a C_(max) of from about 50 ng/mLto about 500 ng/mL. In some cases, the effective amount of the at leastone antiarrhythmic pharmaceutical agent has a C_(max) of from about 100ng/mL to about 250 ng/mL. In some cases, the effective amount of the atleast one antiarrhythmic pharmaceutical agent has an AUC_(Last) of fromabout 100 hr*ng/mL to about 10000 hr*ng/mL. In some cases, the effectiveamount of the at least one antiarrhythmic pharmaceutical agent has anAUC_(Last) of from about 200 ng/mL to about 2000 hr*ng/mL. In somecases, the effective amount of the at least one antiarrhythmicpharmaceutical agent has an AUC_(Last) of from about 500 ng/mL to about800 hr*ng/mL. In some cases, the effective amount of the at least oneantiarrhythmic pharmaceutical agent has an AUC_(Last) of from about 400ng/mL to about 600 hr*ng/mL. In some cases, the effective amount of theat least one antiarrhythmic pharmaceutical agent has a distributiont_(1/2) of from about 0.1 minute to about 15 minutes. In some cases, theeffective amount of the at least one antiarrhythmic pharmaceutical agenthas a distribution t_(1/2) of from about 3 minute to about 4 minutes. Insome cases, the effective amount of the at least one antiarrhythmicpharmaceutical agent has a distribution t_(1/2) of from about 3 minuteto about 5 minutes. In some cases, the effective amount of the at leastone antiarrhythmic pharmaceutical agent has an elimination t_(1/2) offrom about 1 hour to about 25 hours. In some cases, the effective amountof the at least one antiarrhythmic pharmaceutical agent has anelimination t_(1/2) of from about 8.5 hour to about 10.5 hours. In somecases, the effective amount of the at least one antiarrhythmicpharmaceutical agent has a ΔQRS of from about 0.01 msec to about 100msec. In some cases, the effective amount of the at least oneantiarrhythmic pharmaceutical agent has a ΔQRS of from about 1 msec toabout 10 msec. In some cases, the effective amount of the at least oneantiarrhythmic pharmaceutical agent has a ΔQRS of from about 5 msec toabout 20 msec. In some cases, the effective amount of the at least oneantiarrhythmic pharmaceutical agent delivered through the pulmonaryairways by inhalation has a higher ratio of the maximum ΔQRS to theC_(max) as compared to that provided by intravenous delivery of aneffective amount of the at least one antiarrhythmic pharmaceuticalagent. In some cases, the ratio of the maximum ΔQRS to the C_(max)provided by the effective amount of the at least one antiarrhythmicpharmaceutical agent delivered through the pulmonary airways byinhalation is at least 2 folds greater than that provided by intravenousdelivery of an effective amount of the at least one antiarrhythmicpharmaceutical agent. In some cases, the atrial arrhythmia comprisestachycardia. In some cases, the tachycardia comprises supraventriculartachycardia, paroxysmal supraventricular tachycardia, atrialfibrillation, paroxysmal atrial fibrillation, acute episodes inpersistent and permanent atrial fibrillation, atrial flutter, paroxysmalatrial flutter, or lone atrial fibrillation. In some cases, the methodcomprises administering a liquid, dry powder, extruded droplets, ornebulized droplets comprising the at least one antiarrhythmicpharmaceutical agent, wherein the powder or nebulized droplets have amass median aerodynamic diameter of less than 10 μm. In some cases, theantiarrhythmic pharmaceutical agent is a class I antiarrhythmic. In somecases, the class I antiarrhythmic is a class Ia, Ib, or Icantiarrhythmic. In some cases, the class Ic antiarrhythmic isflecainide. In some cases, the antiarrhythmic pharmaceutical agent is aclass II antiarrhythmic. In some cases, the class II antiarrhythmic isesmolol HCl. In some cases, dosage of the esmolol HCl is between 0.5 and0.75 mg/kg body weight. In some cases, the antiarrhythmic pharmaceuticalagent is a class IV antiarrhythmic. In some cases, the class IVantiarrhythmic is diltiazem. In some cases, dosage of the diltiazem is0.25 mg/kg body weight. In some cases, the at least one antiarrhythmicpharmaceutical agent is aerosolized in a nebulizer. In some cases, thenebulizer is a breath-activated nebulizer. In some cases, the nebulizeris a breath-actuated nebulizer. In some cases, the nebulizer isconfigured to administer a liquid pharmaceutical formulation of the atleast one antiarrhythmic pharmaceutical agent. In some cases, theaerosolization occurs at room temperature. In some cases, the at leastone antiarrhythmic pharmaceutical agent is self-administered by thesubject. In some cases, the T_(max), the C_(max), the AUC_(Last), thedistribution t_(1/2), the elimination t_(1/2), or the maximum ΔQRS ofthe effective amount of the at least one antiarrhythmic agent ismeasured in a human PK/PD study. In some cases, the human PK/PD study isa single-dose PK/PD study. In some cases, the human PK/PD study is amulti-dose (e.g., escalating dose) PK/PD study.

In another aspect, disclosed herein is a method of treating a heartcondition, comprising administering a pharmaceutically effective amountof an antiarrhythmic pharmaceutical agent via inhalation to a patient inneed thereof, wherein T_(max) of the pharmaceutically effective amountof the antiarrhythmic pharmaceutical agent after inhalation is fromabout 0.1 minute to about 30 minutes; C_(max) of the pharmaceuticallyeffective amount of the antiarrhythmic pharmaceutical agent afterinhalation is from about 10 ng/mL to about 5000 ng/mL; or AUC_(Last) ofthe pharmaceutically effective amount of the antiarrhythmicpharmaceutical agent after inhalation is from about 100 hr*ng/mL toabout 10000 hr*ng/mL. In some cases, the T_(max) is from about 0.1minute to about 5 minutes, the C_(max) is from about 50 ng/mL to about500 ng/mL, or the AUC_(Last) is from about 200 hr*ng/mL to about 2000hr*ng/mL. In some cases, the T_(max) is from about 0.1 minute to about 5minutes and the C_(max) is from about 50 ng/mL to about 500 ng/mL. Insome cases, the T_(max) is from about 0.1 minute to about 5 minutes andthe AUC_(Last) is from about 200 hr*ng/mL to about 2000 hr*ng/mL. Insome cases, the C_(max) is from about 50 ng/mL to about 500 ng/mL, andthe AUC_(Last) is from about 200 hr*ng/mL to about 2000 hr*ng/mL. Insome cases, the antiarrhythmic pharmaceutical agent is a class I, classII, class III, or class IV antiarrhythmic. In some cases, theantiarrhythmic pharmaceutical agent comprises a class Ic antiarrhythmic.In some cases, the antiarrhythmic pharmaceutical agent comprisesflecainide or a pharmaceutically acceptable salt thereof. In some cases,the method comprises administering 20 mg to 100 mg of flecainide or apharmaceutically acceptable salt thereof via inhalation to the patientin need thereof. In some cases, the method comprises administering 0.25mg/kg body weight to 1.5 mg/kg body weight of flecainide or apharmaceutically acceptable salt thereof via inhalation to the patientin need thereof. In some cases, the antiarrhythmic pharmaceutical agentis delivered over two or more inhalations. In some cases, time betweenthe two or more inhalations is from about 0.1 to 10 minutes.

In another aspect, disclosed herein is a nebulized drug product,comprising a pharmaceutically effective amount of an antiarrhythmicpharmaceutical agent, wherein T_(max) of the pharmaceutically effectiveamount of the antiarrhythmic pharmaceutical agent after inhalation isfrom about 0.1 minute to about 30 minutes; C_(max) of thepharmaceutically effective amount of the antiarrhythmic pharmaceuticalagent after inhalation is from about 10 ng/mL to about 5000 ng/mL; orAUC_(Last) of the pharmaceutically effective amount of theantiarrhythmic pharmaceutical agent after inhalation is from about 100hr*ng/mL to about 10000 hr*ng/mL. In some cases, the T_(max) is fromabout 0.1 minute to about 5 minutes, the C_(max) is from about 50 ng/mLto about 500 ng/mL, or the AUC_(Last) is from about 200 hr*ng/mL toabout 2000 hr*ng/mL. In some cases, the T_(max) is from about 0.1 minuteto about 5 minutes and the C_(max) is from about 50 ng/mL to about 500ng/mL. In some cases, the T_(max) is from about 0.1 minute to about 5minutes and the AUC_(Last) is from about 200 hr*ng/mL to about 2000hr*ng/mL. In some cases, the C_(max) is from about 50 ng/mL to about 500ng/mL, and the AUC_(Last) is from about 200 hr*ng/mL to about 2000hr*ng/mL. In some cases, the antiarrhythmic pharmaceutical agent is aclass I, class II, class III, or class IV antiarrhythmic. In some cases,the antiarrhythmic pharmaceutical agent comprises a class Icantiarrhythmic. In some cases, the antiarrhythmic pharmaceutical agentcomprises flecainide or a pharmaceutically acceptable salt thereof. Insome cases, the nebulized drug product comprises 20 mg to 100 mg offlecainide or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein is a method of manufacturing aformulation for the treatment of a heart condition, comprising apharmaceutically effective amount of an antiarrhythmic pharmaceuticalagent, wherein T_(max) of the pharmaceutically effective amount of theantiarrhythmic pharmaceutical agent after nebulization and inhalation ofthe formulation by a patient in need thereof is from about 0.1 minute toabout 30 minutes; C_(max) of the pharmaceutically effective amount ofthe antiarrhythmic pharmaceutical agent after nebulization andinhalation of the formulation by a patient in need thereof is from about10 ng/mL to about 5000 ng/mL; or AUC_(Last) of the pharmaceuticallyeffective amount of the antiarrhythmic pharmaceutical agent afternebulization and inhalation of the formulation by a patient in needthereof is from about 100 hr*ng/mL to about 10000 hr*ng/mL. In somecases, the T_(max) is from about 0.1 minute to about 5 minutes, theC_(max) is from about 50 ng/mL to about 500 ng/mL, or the AUC_(Last) isfrom about 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, theT_(max) is from about 0.1 minute to about 5 minutes and the C_(max) isfrom about 50 ng/mL to about 500 ng/mL. In some cases, the T_(max) isfrom about 0.1 minute to about 5 minutes and the AUC_(Last) is fromabout 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the C_(max) isfrom about 50 ng/mL to about 500 ng/mL, and the AUC_(Last) is from about200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the antiarrhythmicpharmaceutical agent is a class I, class II, class III, or class IVantiarrhythmic. In some cases, the antiarrhythmic pharmaceutical agentcomprises a class Ic antiarrhythmic. In some cases, the antiarrhythmicpharmaceutical agent comprises flecainide or a pharmaceuticallyacceptable salt thereof. In some cases, the antiarrhythmicpharmaceutical agent is delivered over two or more inhalations. In somecases, time between the two or more inhalations is from about 0.1 to 10minutes.

In another aspect, disclosed herein is a nebulized drug product,comprising a pharmaceutically effective amount of an antiarrhythmicpharmaceutical agent for use in treating a heart condition, whereinT_(max) of the pharmaceutically effective amount of the antiarrhythmicpharmaceutical agent after inhalation is from about 0.1 minute to about30 minutes; C_(max) of the pharmaceutically effective amount of theantiarrhythmic pharmaceutical agent after inhalation is from about 10ng/mL to about 5000 ng/mL; or AUC_(Last) of the pharmaceuticallyeffective amount of the antiarrhythmic pharmaceutical agent afterinhalation is from about 100 hr*ng/mL to about 10000 hr*ng/mL. In somecases, the T_(max) is from about 0.1 minute to about 5 minutes, theC_(max) is from about 50 ng/mL to about 500 ng/mL, or the AUC_(Last) isfrom about 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, theT_(max) is from about 0.1 minute to about 5 minutes and the C_(max) isfrom about 50 ng/mL to about 500 ng/mL. In some cases, the T_(max) isfrom about 0.1 minute to about 5 minutes and the AUC_(Last) is fromabout 200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the C_(max) isfrom about 50 ng/mL to about 500 ng/mL, and the AUC_(Last) is from about200 hr*ng/mL to about 2000 hr*ng/mL. In some cases, the antiarrhythmicpharmaceutical agent is a class I, class II, class III, or class IVantiarrhythmic. In some cases, the antiarrhythmic pharmaceutical agentcomprises a class Ic antiarrhythmic. In some cases, the antiarrhythmicpharmaceutical agent comprises flecainide or a pharmaceuticallyacceptable salt thereof. In some cases, the nebulized drug productcomprises 20 mg to 100 mg of flecainide or a pharmaceutically acceptablesalt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is further described in the description ofinvention that follows, in reference to the noted plurality ofnon-limiting drawings, wherein:

FIG. 1 shows how prior art intravenous drug passes through the heart andlungs before reaching coronary arteries, hence coronary circulation.

FIG. 2A shows how inhaled drug of the present invention passes throughdirectly from the lungs to the left atrium, left ventricle and then intothe coronary arteries.

FIG. 2B shows how inhaled drug of the present invention passes throughthe pulmonary vein to the left atrium.

FIG. 3 shows that molecules with high Log-P values and those that havehigh lipid solubility are likely to exhibit faster absorption throughthe lung.

FIG. 4 shows a six compartment PK-PD model to compare intravenous andpulmonary delivery.

FIG. 5 shows the results of a simulation comparing intravenous andpulmonary delivery of verapamil.

FIG. 6 shows the results of a simulation comparing intravenous andpulmonary delivery of lidocaine.

FIG. 7 shows a representative study outline: effects of flecainide (FLE,n=2), diltiazem (DIL, n=2), and dofetilide (DOF, n=2) on inducedatrial-fibrillation. NSR: normal sinus rhythm.

FIG. 8 shows a representative study outline: dose-response ofintratracheal (IT) esmolol HCL (ESM, n<=2) or adenosine (ADN, n<=2) oninduced supra-ventricular tachycardia (SVT). NSR: normal sinus rhythm.IV: intravenous

FIG. 9 shows an ECG trace showing Dog in Afib prior to dosing of eithervehicle or test article.

FIG. 10 shows an ECG trace showing Dog continues to be in Afib afterpulmonary administration of vehicle (water, 3 ml).

FIG. 11 shows an ECG trace showing the Afib converting into normal sinusrhythm when a dog was administered 4 mg/kg body weight of Flecainideacetate by intra-tracheal instillation.

FIG. 12 shows an ECG trace showing Afib converting as soon as dosingoccurred at 2 mg/kg body weight of flecainide acetate.

FIG. 13 shows an ECG trace showing Afib converting after administrationof diltiazem HCl at 0.25 mg/kg body weight.

FIG. 14 shows results from a supraventricular tachycardia model in whichPR interval and Mean Arterial blood pressure (MAP) change in time afterpulmonary administration of pulmonary diltiazem 0.25 mg/kg.

FIG. 15 shows results from the supraventricular tachycardia model inwhich PR interval and Mean Arterial blood pressure (MAP) change in timeafter intravenous administration of pulmonary diltiazem 0.25 mg/kg.

FIG. 16 shows results from the supraventricular tachycardia modelshowing effect on PR interval over time of 0.5 mg/kg body weight ofesmolol HCl administered via the lung (IT).

FIG. 17 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.5 mg/kg administered viathe lung.

FIG. 18 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.5 mg/kg administered viathe lung.

FIG. 19 shows results from the supraventricular tachycardia modelshowing effect on PR interval over time of 0.5 mg/kg body weight ofesmolol HCl administered via the lung (IT).

FIG. 20 shows results from the supraventricular tachycardia modelshowing period of AV block induced by esmolol 0.75 mg/kg administeredvia the lung.

FIG. 21 shows the design for the Phase 1 clinical study.

FIG. 22 shows the time course of the changes in the heart rate (ΔHR)relative to the baseline (pre-dose) following oral inhalation of 20 mgeTLD (estimated Total Lung Dose) of flecainide acetate solution andplacebo in subjects of Cohort 1. Values are the mean±standard error ofthe mean (SEM).

FIG. 23 shows the changes in heart rate (ΔHR) following inhalation of 40mg eTLD of flecainide acetate and placebo solutions in subjects ofCohort 2 relative to pre-dose values. Values are the mean±SEM.

FIG. 24 shows the heart rate (bpm) of subjects in Cohort 5 followingoral inhalation (IH) of flecainide acetate solution (30 mg eTLD) andadministration of flecainide acetate solution by IV (2 mg/kg). Valuesare the mean±standard deviation (SD).

FIG. 25A shows changes in systolic blood pressure (BP) from subjects ofCohort 1 following inhalation of 20 mg eTLD of flecainide acetate andplacebo solutions.

FIG. 25B shows changes in diastolic BP from subjects of Cohort 1following inhalation of 20 mg eTLD of flecainide acetate and placebosolutions.

FIG. 26A shows changes in systolic BP from subjects of Cohort 2following inhalation of 40 mg eTLD of flecainide acetate and placebosolutions.

FIG. 26B shows changes in diastolic BP from subjects of Cohort 2following inhalation of 40 mg eTLD of flecainide acetate and placebosolutions.

FIG. 27A shows changes in systolic BP from subjects of Cohort 5following single dose administration of inhaled (IH) flecainide (30 mgeTLD) and IV flecainide (2 mg/kg). Values are the mean±SD.

FIG. 27B shows changes in diastolic BP from subjects of Cohort 5following single dose administration of inhaled (IH) flecainide (30 mgeTLD) and IV flecainide (2 mg/kg). Values are the mean±SD.

FIG. 28 shows mean venous plasma concentration-time curves followinginhalation of 20 mg eTLD, 30 mg eTLD, and 40 mg eTLD of flecainideacetate solution.

FIG. 29A shows the mean venous plasma concentration-time curve followingadministration of flecainide acetate solution by IV (2 mg/kg). Datapoints represent the mean±SD.

FIG. 29B shows mean venous plasma concentration-time curves followingadministration of flecainide acetate solution by inhalation (IH; 30 mgeTLD) or IV (2 mg/kg). Data points represent the mean±SD.

FIG. 30 shows the time course of the changes in PR interval duration(ΔPR) relative to the baseline (pre-dose) following oral inhalation of20 mg eTLD of flecainide acetate solution and acetate buffer (placebo).Values are the mean±SEM; n=6 (flecainide), n=2 (placebo).

FIG. 31 shows the time course of the changes in QRS interval duration(ΔQRS) relative to the baseline (pre-dose) following oral inhalation of20 mg eTLD of flecainide acetate solution and placebo. Values are themean±SEM; n=6 (flecainide), n=2 (placebo).

FIG. 32 shows the time course of the changes in QRS interval duration(ΔQRS) relative to the baseline (pre-dose) following oral inhalation of40 mg eTLD of flecainide acetate solution and placebo. Values are themean±SEM; n=10 (flecainide), n=4 (placebo).

FIG. 33A shows selected digitized electrocardiographic (ECG) tracingsfrom lead V5 depicting the P-, QRS- and T-wave complexes recorded priorto (pre-dose) and at various times after (post-dose) completion ofinhalation of 40 mg eTLD of flecainide. Denoted in each panel are thevalues of the QRS interval duration in milliseconds (QRSd, ms) andR-wave amplitude in microvolts (QRSa, μV).

FIG. 33B shows bar graphs summarizing the time course of changes in QRSinterval duration measured from ECGs at the respective times andobtained from the same subject in FIG. 13A. * p<0.05.

FIG. 33C shows bar graphs summarizing the time course of changes inR-wave amplitude measured from ECGs at the respective times and obtainedfrom the same subject in FIG. 13A. * p<0.05.

FIG. 34 shows the changes in QRS interval duration (ΔQRS) relative tothe baseline (pre-dose) in subjects of Cohort 5 (IV-inhalationcrossover) following A) administration of flecainide acetate solution byIV (2 mg/kg; *10 min infusion, intraventricular conduction delay lasted5-10 min) and B) oral inhalation of 30 mg eTLD of flecainide acetatesolution (**4 min inhalation).

FIG. 35 shows the time course of the changes in the QTcF intervalduration (ΔQTcF) relative to the baseline (pre-dose) following oralinhalation of 20 mg eTLD of flecainide acetate solution and placebo.Values are the mean±SEM; n=6 (flecainide), n=2 (placebo).

FIG. 36 shows ECG tracings recorded from a subject administeredflecainide (2 mg/kg) by IV. Small arrows on the electrogram indicate theT-wave.

FIG. 37 shows venous plasma concentrations of flecainide administered IVor orally at the time of cardioversion of atrial fibrillation (AF) inpatients with recent onset AF (left panel), following oral inhalation of40 mg eTLD of flecainide acetate solution by healthy volunteers (centerpanel), and at the time of conversion of AF to NSR in dogs followingintratracheal (IT) instillation of 0.75 mg/kg of flecainide (rightpanel). LV=Left Ventricle; * Mean±SD of plasma concentration(×1.96-fold) extrapolated from animal studies in dogs at time ofcardioversion.

FIG. 38 shows comparative ΔQRS interval prolongation (msec) associatedwith the administration of flecainide or vemakalant at the time ofcardioversion of AF in patients with recent onset AF and following oralinhalation of 30 mg eTLD of flecainide acetate solution by healthyvolunteers.

FIGS. 39-67 refer to data obtained in pigs. FIG. 39 shows flecainidevenous and left ventricular chamber (LV) plasma levels at different timepoints following intravenous administration of 2.0 mg/kg over 2 min.

FIG. 40 shows flecainide venous and LV plasma levels at different timepoints following intratracheal instillation of 0.75 mg/kg.

FIG. 41 shows flecainide venous and LV plasma levels at different timepoints following intratracheal instillation of 1.5 mg/kg.

FIG. 42 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on heart rate (primary vertical axis) and LV plasma levels(secondary vertical axis) at different time points.

FIG. 43 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on mean arterial blood pressure (MAP; primary vertical axis)and LV plasma levels (secondary vertical axis) at different time points.

FIG. 44 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on the PR interval duration (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 45 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on QRS interval duration (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 46 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on the QTc interval duration (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 47 shows the effects of intravenous administration of flecainide(2.0 mg/kg) on the JTc interval duration (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 48 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on heart rate (primary vertical axis)and LV plasma levels (secondary vertical axis) at different time points.

FIG. 49 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on MAP (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 50 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on the PR interval (primary verticalaxis) and LV plasma levels (secondary vertical axis) at different timepoints.

FIG. 51 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on QRS interval duration (primaryvertical axis) and LV plasma levels (secondary vertical axis) atdifferent time points.

FIG. 52 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on the QTc interval (primary verticalaxis) and LV plasma levels (secondary vertical axis) at different timepoints.

FIG. 53 shows the effects of intratracheal instillation of the lowerdose of flecainide (0.75 mg/kg) on the JTc interval (primary verticalaxis) and LV plasma level (secondary vertical axis) at different timepoints.

FIG. 54 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on heart rate (primary vertical axis) andLV plasma levels (secondary vertical axis) at different time points.

FIG. 55 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on MAP (primary vertical axis) and LVplasma levels (secondary vertical axis) at different time points.

FIG. 56 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on the PR interval (primary verticalaxis) and LV plasma levels (secondary vertical axis) at different timepoints.

FIG. 57 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on QRS interval duration (primaryvertical axis) and LV plasma levels (secondary vertical axis) atdifferent time points.

FIG. 58 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on the QTc interval (primary verticalaxis) and LV plasma levels (secondary vertical axis) at different timepoints.

FIG. 59 shows the effects of intratracheal instillation of the higherdose of flecainide (1.5 mg/kg) on the JTc interval (primary verticalaxis) and LV plasma levels (secondary vertical axis) at different timepoints.

FIG. 60 shows the protocol and a representative example of induction ofatrial fibrillation (AF) to test conversion by IT flecainide.

FIG. 61 shows a summary of the data from experiments evaluating theeffects of intratracheal instillation of flecainide (1.5 mg/kg) on AFduration (n=3).

FIG. 62A shows the effects of slow versus rapid infusion of IVadministered flecainide on the venous plasma levels of flecainide.

FIG. 62B shows the effects of slow versus rapid infusion of IVadministered flecainide on the QRS interval duration.

FIG. 62C shows the correlation between venous plasma levels of slowlyversus rapidly infused, IV administered flecainide and QRS widening.

FIG. 63 shows catheter placement in anesthetized Yorkshire pigs.

FIG. 64 shows AF duration was correlated with IT flecainide dose.

FIG. 65 shows representative electrograms demonstrating AF conversion at5 min after IT flecainide (1.5 mg/kg) (lower panel) compared to noconversion by 10 min after no drug (upper panel).

FIG. 66A shows the plasma concentration of flecainide reached levelsrequired for conversion of AF to NSR within 10 min after IT flecainide(0.75 mg/kg and 1.5 mg/kg).

FIG. 66B shows the plasma concentrations of flecainide at the time ofconversion of AF to NSR following IT instillation of flecainide (0.75mg/kg and 1.5 mg/kg).

FIG. 67 shows the reduction in the dominant frequency of AF by ITflecainide (0.75 mg/kg and 1.5 mg/kg).

FIGS. 68A-71 refer to data obtained in dogs. FIG. 68A shows arepresentative ECG demonstrating AF prior to dosing.

FIG. 68B shows a representative ECG demonstrating persistence of AFafter IT instillation of vehicle.

FIG. 68C shows a representative ECG demonstrating AF prior to dosing.

FIG. 68D shows a representative ECG demonstrating conversion of AF toNSR following IT flecainide (0.75 mg/kg).

FIG. 69 shows a summary of the changes in blood pressure, ventricularrate, and LV dP/dT_(max) (the maximal rate of rise of LV pressure) uponconversion of AF to NSR following administration of flecainide via IV orIT.

FIG. 70 shows the variations in plasma concentrations of flecainide inthe left ventricular chamber (LV), pulmonary artery (PA), and femoralvein (VEN) based on the route of delivery (IT and IV) of flecainide.Note that following IV infusion, the concentrations of flecainide in thePA were transiently higher (2.1- to 3.5-fold)* than those in the LV.After IT instillation of flecainide, its concentrations were transientlyhigher (1.4- to 3.2-fold)* in the LV chamber than in the PA (*between 1to 3 min after administration of flecainide).

FIG. 71 shows the time course of the ratios of the plasma concentrationsof flecainide in the pulmonary artery (PA) and left ventricular chamber(LV) following IV or IT administration.

FIGS. 72-87B refer to data obtained in human subjects. FIG. 72 shows theeffects of postural changes and inhalation of flecainide or placebo(n=3) on heart rate (HR) at different time points.

FIG. 73 shows the effects of intravenously delivered (IV) flecainide onsystolic blood pressure and heart rate in 6 subjects at different timepoints.

FIG. 74 shows the effects of inhaled flecainide on systolic bloodpressure and heart rate in 6 subjects at different time points.

FIG. 75A shows systolic and diastolic blood pressures followingflecainide intravenous delivery in 6 subjects.

FIG. 75B shows systolic and diastolic blood pressures followingflecainide inhalation (IH) administration in 6 subjects.

FIGS. 76A and 76B show venous plasma concentration-time curves of theper-protocol population and post-hoc population following oralinhalation of 20, 40, and 60 mg eTLD flecainide, respectively.

FIGS. 77A and 77B show venous plasma concentration-time curves followingintravenous infusion and inhalation of flecainide, respectively.

FIG. 78 shows venous plasma concentration-time curve followingflecainide IV infusion (normalized to 30 mg eTLD dose) and oralinhalation.

FIG. 79 shows time course of changes in QRS interval duration withflecainide or placebo.

FIGS. 80A and 80B show time courses of changes in QRS interval durationfollowing flecainide via IV infusion and oral inhalation, respectively.

FIG. 81 shows time course of changes in PR interval duration withflecainide or placebo.

FIGS. 82A and 82B show time courses of changes in PR interval followingflecainide IV infusion and oral inhalation, respectively.

FIG. 83 shows relationship between peak venous plasma concentrations offlecainide (C_(max)) and the magnitude of maximal QRS prolongation.

FIGS. 84A and 84B show time courses of changes in plasma concentrationsof flecainide and QRS duration with flecainide IV infusion and oralinhalation, respectively.

FIG. 85 shows non-steady state relationships between plasmaconcentration of flecainide and QRS duration following flecainide IVinfusion and oral inhalation, respectively.

FIG. 86 shows non-steady state relationships between plasmaconcentrations of flecainide and QRS duration following flecainide IVinfusion and oral inhalation in subjects with near-equal ΔQRS values.

FIG. 87A shows baseline (pre-dose) values of heart rate, systolic bloodpressure (BP), and diastolic BP in Periods 1 and 2 of 6 subjects in PartB study.

FIG. 87B shows baseline (pre-dose) values of QRS complexes and PRintervals in Periods 1 and 2 of 6 subjects in Part B study.

DETAILED DESCRIPTION

It is to be understood that unless otherwise indicated the presentinvention is not limited to specific formulation components, drugdelivery systems, manufacturing techniques, administration steps, or thelike, as such may vary. In this regard, unless otherwise stated, areference to a compound or component includes the compound or componentby itself, as well as the compound or component in combination withother compounds or components, such as mixtures of compounds.

Before further discussion, a definition of the following terms will aidin the understanding of the present invention.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an antiarrhythmic pharmaceutical agent” includesnot only a single active agent but also a combination or mixture of twoor more different active agents.

Reference herein to “one embodiment,” “one version,” or “one aspect”shall include one or more such embodiments, versions or aspects, unlessotherwise clear from the context.

As used herein, the term “solvate” is intended to include, but not belimited to, pharmaceutically acceptable solvates.

As used herein, the term “pharmaceutically acceptable solvate” isintended to mean a solvate that retains one or more of the biologicalactivities and/or properties of the antiarrhythmic pharmaceutical agentand that is not biologically or otherwise undesirable. Examples ofpharmaceutically acceptable solvates include, but are not limited to,antiarrhythmic pharmaceutical agents in combination with water,isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,ethanolamine, or combinations thereof.

As used herein, the term “salt” is intended to include, but not belimited to, pharmaceutically acceptable salts.

As used herein, the term “pharmaceutically acceptable salt” is intendedto mean those salts that retain one or more of the biological activitiesand properties of the free acids and bases and that are not biologicallyor otherwise undesirable. Illustrative examples of pharmaceuticallyacceptable salts include, but are not limited to, sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, di nitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenyipropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

If the antiarrhythmic pharmaceutical agent is a base, the desired saltmay be prepared by any suitable method known in the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such asglucuronic acid and galacturonic acid, alpha-hydroxy acids such ascitric acid and tartaric acid, amino acids such as aspartic acid andglutamic acid, aromatic acids such as benzoic acid and cinnamic acid,sulfonic acids such as p-toluenesulfonic acid and ethanesulfonic acid,or the like.

If the antiarrhythmic pharmaceutical agent is an acid, the desired saltmay be prepared by any suitable method known in the art, includingtreatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal or alkalineearth metal hydroxide, or the like. Illustrative examples of suitablesalts include organic salts derived from amino acids such as glycine andarginine, ammonia, primary, secondary and tertiary amines, and cyclicamines such as piperidine, morpholine and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum and lithium.

The term “about” in relation to a reference numerical value can includea range of values plus or minus 10% from that value. For example, theamount “about 10” includes amounts from 9 to 11, including the referencenumbers of 9, 10, and 11. The term “about” in relation to a referencenumerical value can also include a range of values plus or minus 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

As used herein, “atrial arrhythmia” can mean an arrhythmia that affectsat least one atrium and does not include bradycardia. For instance,atrial arrhythmia may originate in and affect at least one atrium.

As used herein, “tachycardia” can mean an arrhythmia in which the heartbeat is too fast, e.g., faster than normal. For instance, tachycardiamay involve a resting heart rate of over 100 beats per minute, such asgreater than 110, greater than 120, or greater than 130 beats minute.

As used herein, the phrase “heart rhythm arrhythmia” can mean anarrhythmia in which the heart beat is irregular.

As used herein, the “amount of the at least one antiarrhythmicpharmaceutical agent in blood in the coronary circulation of the heart”may be measured by extracting a sample from any vascular region of thecoronary circulation of the heart (e.g., arteries, veins, includingcoronary sinus) by using a cannula. The amount of antiarrhythmicpharmaceutical agent in the sample may then be determined by knownmeans, such as bioanalytical techniques that employ analytical equipmentsuch as LC-MS/MS. Thus, the amount of antiarrhythmic pharmaceuticalagent in the blood in the heart may be measured for any particular time.

As used herein, the terms “treating” and “treatment” can refer toreduction in severity and/or frequency of symptoms, elimination ofsymptoms and/or underlying cause, reduction in likelihood of theoccurrence of symptoms and/or underlying cause, and/or remediation ofdamage. Thus, “treating” a patient with an active agent as providedherein includes prevention of a particular condition, disease, ordisorder in a susceptible individual as well as treatment of aclinically symptomatic individual.

As used herein, “nominal amount” can refer to the amount containedwithin the unit dose receptacle(s) that are administered.

As used herein, “effective amount” can refer to an amount covering boththerapeutically effective amounts and prophylactically effectiveamounts.

As used herein, a “therapeutically effective amount” of an active agentrefers to an amount that is effective to achieve a desired therapeuticresult. A therapeutically effective amount of a given active agent willtypically vary with respect to factors such as the type and severity ofthe disorder or disease being treated and the age, gender, and weight ofthe patient. In some cases, “inhalation” (e.g., “oral inhalation”) canrefer to inhalation delivery of a therapeutically effective amount of apharmaceutical agent contained in one unit dose receptacle, which, insome instance, can require one or more breaths, like 1, 2, 3, 4, 5, 6,7, 8, 9, or more breaths. For example, if the effective amount is 90 mg,and each unit dose receptacle contains 30 mg, the delivery of theeffective amount can require 3 inhalations.

Unless otherwise specified, the term “therapeutically effective amount”can include a “prophylactically effective amount,” e.g., an amount ofactive agent that is effective to prevent the onset or recurrence of aparticular condition, disease, or disorder in a susceptible individual.

As used herein, the phrase “minimum effective amount” can mean theminimum amount of a pharmaceutical agent necessary to achieve aneffective amount.

As used herein, “mass median diameter” or “MMD” can refer to the mediandiameter of a plurality of particles, typically in a polydisperseparticle population, e.g., consisting of a range of particle sizes. MMDvalues as reported herein are determined by laser diffraction (SympatecHelos, Clausthal-Zellerfeld, Germany), unless the context indicatesotherwise. For instance, for powders the samples are added directly tothe feeder funnel of the Sympatec RODOS dry powder dispersion unit. Thiscan be achieved manually or by agitating mechanically from the end of aVIBRI vibratory feeder element. Samples are dispersed to primaryparticles via application of pressurized air (2 to 3 bar), with vacuumdepression (suction) maximized for a given dispersion pressure.Dispersed particles are probed with a 632.8 nm laser beam thatintersects the dispersed particles' trajectory at right angles. Laserlight scattered from the ensemble of particles is imaged onto aconcentric array of photomultiplier detector elements using areverse-Fourier lens assembly. Scattered light is acquired intime-slices of 5 ms. Particle size distributions are back-calculatedfrom the scattered light spatial/intensity distribution using aproprietary algorithm.

As used herein, “geometric diameter” can refer to the diameter of asingle particle, as determined by microscopy, unless the contextindicates otherwise.

As used herein, “mass median aerodynamic diameter” or “MMAD” can referto the median aerodynamic size of a plurality of particles or particles,typically in a polydisperse population. The “aerodynamic diameter” canbe the diameter of a unit density sphere having the same settlingvelocity, generally in air, as a powder and is therefore a useful way tocharacterize an aerosolized powder or other dispersed particle orparticle formulation in terms of its settling behavior. The aerodynamicdiameter encompasses particle or particle shape, density, and physicalsize of the particle or particle. As used herein, MMAD refers to themedian of the aerodynamic particle or particle size distribution ofaerosolized particles determined by cascade impaction, unless thecontext indicates otherwise.

As used herein, the term “emitted dose” or “ED” can refer to anindication of the delivery of particles from an aerosolization deviceafter an actuation or dispersion event from a unit dose receptacle orreservoir. ED is defined as the ratio of the dose delivered by aninhaler device to the nominal dose (e.g., the mass of powder or liquidper unit dose placed into a suitable inhaler device prior to firing).The ED is an experimentally determined amount, and may be determinedusing an in vitro system that mimics patient dosing. For instance, todetermine an ED value for a dry powder, a nominal dose of dry powder isplaced into a Turbospin® DPI device (PH&T, Italy), described in U.S.Pat. Nos. 4,069,819 and 4,995,385, which are incorporated herein byreference in their entireties. The Turbospin® DPI is actuated,dispersing the powder. The resulting aerosol cloud is then drawn fromthe device by vacuum (30 L/min) for 2.5 seconds after actuation, atwhich point it is captured on a tared glass fiber filter (Gelman, 47 mmdiameter) attached to the device mouthpiece. The amount of powder thatreaches the filter constitutes the delivered dose. For example, for acapsule containing 5 mg of dry powder, capture of 4 mg of powder on thetared filter would indicate an ED of 80% (=4 mg (delivered dose)/5 mg(nominal dose)).

As used herein, “passive dry powder inhaler” can refer to an inhalationdevice that relies upon a patient's inspiratory effort to disperse andaerosolize a pharmaceutical composition contained within the device in areservoir or in a unit dose form and does not include inhaler deviceswhich comprise a means for providing energy, such as pressurized gas andvibrating or rotating elements, to disperse and aerosolize the drugcomposition.

As used herein, “active dry powder inhaler” can refer to an inhalationdevice that does not rely solely on a patient's inspiratory effort todisperse and aerosolize a pharmaceutical composition contained withinthe device in a reservoir or in a unit dose form and does includeinhaler devices that comprise a means for providing energy to disperseand aerosolize the drug composition, such as pressurized gas andvibrating or rotating elements.

By a “pharmaceutically acceptable” component is meant a component thatis not biologically or otherwise undesirable, e.g., the component may beincorporated into a pharmaceutical formulation of the invention andadministered to a patient as described herein without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the formulationin which it is contained. When the term “pharmaceutically acceptable” isused to refer to an excipient, it is generally implied that thecomponent has met the required standards of toxicological andmanufacturing testing or that it is included on the Inactive IngredientGuide prepared by the U.S. Food and Drug Administration.

As used herein, “P wave” can represent the wave generated by theelectrical depolarization of the atria (right and left), and is usually0.08 to 0.1 seconds (80-100 ms) in duration.

As used herein, “short form-36 quality of life” can mean the Short Form36 (SF-36) survey of patient health (updated August 2005). The SF-36consists of eight scaled scores, which are the sums of the questions intheir section. Each scale is directly transformed into a 0-100 scale onthe assumption that each question carries equal weight. The eightsections are: (1) vitality; (2) physical functioning; (3) bodily pain;(4) general health perceptions; (5) physical role functioning; (6)emotional role functioning; (7) social role functioning; and (8) mentalhealth. It can also refer to any Quality of Life questionnaire for AFsympotoms.

As used herein, “preservative” can mean cresols and benzoates. Thus,“substantially preservative-free” can mean that a composition does notinclude a substantial amount of any cresols and/or benzoates. Forinstance, “substantially preservative-free” compositions can compriseless than 1 wt %, such as less than 0.5 wt %, less than 0.4 wt %, lessthan 0.3 wt %, less than 0.2 wt %, or less than 0.1 wt %, ofpreservative. Of course, “preservative-free” can mean that nopreservative is present.

As used herein, “substantially tasteless” can mean a composition thathas substantially little to no taste upon initial ingestion.

As an overview, the present invention relates to methods of treatingatrial arrhythmia. The methods may comprise administering an effectiveamount of at least one antiarrhythmic pharmaceutical agent to a patientin need thereof, such that the at least one antiarrhythmicpharmaceutical agent first enters the heart through the pulmonary veinsto the left atrium.

In one aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an amount of the at least one antiarrhythmic pharmaceuticalagent peaks in the coronary circulation of the heart at a time rangingfrom 10 seconds to 30 minutes from the administration.

In yet another aspect, the present invention is directed to a method ofself-diagnosing and treating atrial arrhythmia. The method comprisesself-diagnosing atrial arrhythmia by detecting at least one of shortnessof breath, heart palpitations, and above normal heart rate. The methodalso comprises self-administering by inhalation an effective amount ofat least one antiarrhythmic pharmaceutical agent within two hours, onehour, 30 minutes, or 15 minutes of the self-diagnosing. In some cases,the method comprises self-administering by inhalation an effectiveamount of at least one antiarrhythmic pharmaceutical agent within 15minutes of the self-diagnosing.

In another aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein an electrophysiologic effect is observed, viaelectrocardiography, at a time ranging from 10 seconds to 30 minutesfrom the administration.

In still another aspect, a method of treating atrial arrhythmiacomprises administering by inhalation an effective amount of at leastone antiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a cardiac score from a monitor implementing an arrhythmiadetection algorithm shows a transition from an arrhythmic state tonormal sinus rhythm in the patient at a time ranging from 10 seconds to30 minutes from the administration.

In yet another aspect, a method of treating atrial arrhythmia comprisesadministering by inhalation an effective amount of at least oneantiarrhythmic pharmaceutical agent to a patient in need thereof,wherein a short form-36 quality of life score of the patient improves ata time ranging from 10 seconds to 30 minutes from the administration.

In another aspect, a unit dose comprises a unit dose receptacle and acomposition within the unit dose receptacle. The composition comprisesat least one antiarrhythmic pharmaceutical agent in an amount less thanor equal to an amount of the same at least one antiarrhythmicpharmaceutical agent administered intravenously in the arm to achieve aminimum effective amount in the coronary circulation, and apharmaceutically acceptable excipient.

In still another aspect, an aerosol comprises particles having a massmedian aerodynamic diameter less than 10 μm. The particles comprise atleast one antiarrhythmic pharmaceutical agent in an amount less than orequal to an amount of the same at least one antiarrhythmicpharmaceutical agent administered intravenously in the arm to achieve aminimum effective amount in the coronary circulation, and apharmaceutically acceptable excipient.

In yet another aspect, a kit comprises a container containing at leastone antiarrhythmic pharmaceutical agent and an aerosolization device.

In certain embodiments, the present invention includes“pharmaco-rescue-therapies” to provide fast cardioversion in patientswith atrial arrhythmias like Paroxysmal Ventricular Tachycardia (PSVT),and Paroxysmal Atrial Fibrillation (PAF). The pharmaco-rescue-therapiesare usually intended for self-administration of the medicine byinhalation.

Inhalation is the shortest route for a drug to reach the heart, nextonly to intracardiac injection, as shown in FIGS. 2A and 2B. Drugsdelivered by inhalation generally exhibit “pulsatile pharmacokinetics”of transient high drug concentrations, followed by dilution tosub-therapeutic levels.

Thus, in some embodiments, the present invention involves a rapid actinginhaled product with a fast onset of action compared to oral medicine.The product is expected to be at least as fast as intravenous medicine.In some embodiments, an amount of the at least one antiarrhythmicpharmaceutical agent peaks in the coronary circulation of the heart at atime ranging from 10 seconds to 30 minutes, such as 30 seconds to 20minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutesto 5 minutes, from the administration. In certain embodiments, anelectrophysiologic effect is observed, via electrocardiography, at atime ranging from 10 seconds to 30 minutes, such as 30 seconds to 20minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutesto 5 minutes, from the administration. In some embodiments, a cardiacscore from a device with an arrhythmia detection algorithm shows atransition from an arrhythmic state to normal sinus rhythm in thepatient at a time ranging from 10 seconds to 30 minutes, such as 30seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes,or 2.5 minutes to 5 minutes, from the administration. In someembodiments, a short form-36 quality of life score of the patientimproves at a time ranging from 10 seconds to 30 minutes, such as 30seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes,or 2.5 minutes to 5 minutes, from the administration. In certainembodiments, the patient has normal sinus rhythm within 30 minutes, suchas within 10 minutes, of initiating the administering.

In some aspects, the present invention involves low doses that are safeand effective. Other aspects typically involve low premature metabolismand low drug-drug interaction.

The present invention includes non-invasive drug delivery to the heart.The lung is shortest route for drug to heart with minimal dilution nextto intra-cardiac injection. Drugs delivered via the lung have a fastonset action compared to those delivered via the oral route. PipelineInsights: Antiarrhythmics, Datamonitor (June 2006). Pulmonary drugdelivery to the heart is at least equivalent to a portable intravenousinjection. Inhaled drugs (e.g., verapamil, diltiazem, lidocaine,ibutilide, procainamide, and propafenone) are expected to exhibit“pulsatile pharmacokinetics” of transient high drug concentrations,followed by dilution to sub-therapeutic levels.

Existing cardiovascular drugs tend to be small molecules with high lipidsolubility. These lipid soluble molecules (e.g., diltiazem, verapamil,ibutilide, propafenone) are expected to have a high pulmonarybioavailability and fast rate of pulmonary absorption. This ensures thatthey reach the heart through the pulmonary veins.

The pulsatile pharmacokinetic behavior of the drugs show that the drugis diluted within a few seconds of reaching effective concentrations inthe heart and is diluted to sub-therapeutic levels in the volume of theblood. This characteristic will minimize drug-drug interactions thatproduce significant toxicological responses normally seen at steadystate.

Thus, in certain embodiments, the present invention relates to achievingtransient high drug concentrations in the heart that effect rate andrhythm changes in the heart within a short period of time allowing fortreatment of episodic arrhythmias such as paroxysmal atrial arrhythmias.

The results of the invention are surprising and unexpected. In thisregard, the antiarrhythmic pharmaceutical agents pass through the lungsquickly. For instance, verapamil and diltiazem will ionize if in saltform, so the base will pass through the lungs quickly. In some aspects,the methods of the present invention take advantage of fast onset ofaction, high drug bioavailability, and fast absorption through the lung.Most cardiovascular drugs are small molecules that have high lipidsolubility and are therefore expected to have high pulmonarybioavailability and a fast rate of absorption. FIG. 3 shows the log-pvalues and lipid solubility of exemplary cardiovascular molecules alongwith their expected high pulmonary bioavailability.

Another reason why the results of the present invention are surprisingand unexpected involves the rate at which the antiarrhythmicpharmaceutical agents pass through the heart. While a skilled artisanmight expect the rate to be too fast, modeling indicates that the drugwill not pass through the heart too fast. Thus, a therapeutic effect isachieved despite fast pass-through and despite only one pass-through attherapeutic levels.

In view of the above, in one or more embodiments of the invention, acomposition comprises an antiarrhythmic pharmaceutical agent. Examplesof antiarrhythmic pharmaceutical agents include, but are not limited to,class Ia (sodium channel blockers, intermediateassociation/dissociation), class Ib (sodium channel blockers, fastassociation/dissociation), class Ic (sodium channel blocker, slowassociation/dissociation), class II (beta blockers), class III(potassium channel blockers), class IV (calcium channel blockers), andclass V (unknown mechanisms) antiarrhythmics.

Class Ia antiarrhythmics include, but are not limited to, quinidine,procainamide, and disopyramide, and pharmaceutically acceptable saltsthereof. Class Ib antiarrhythmics include, but are not limited to,lidocaine, tocainide, phenytoin, moricizine, and mexiletine, andpharmaceutically acceptable salts thereof. Class Ic antiarrhythmicsinclude, but are not limited to, flecainide, propafenone, andmoricizine, and pharmaceutically acceptable salts thereof. Class IIantiarrhythmics include, but are not limited to, propranolol,acebutolol, soltalol, esmolol, timolol, metoprolol, and atenolol, andpharmaceutically acceptable salts thereof. Class III antiarrhythmicsinclude, but are not limited to, amiodarone, sotalol, bretylium,ibutilide, E-4031 (methanesulfonamide), vernakalant, and dofetilide, andpharmaceutically acceptable salts thereof. Class IV antiarrhythmicsinclude, but are not limited to, bepridil, nitrendipine, amlodipine,isradipine, nifedipine, nicardipine, verapamil, and diltiazem, andpharmaceutically acceptable salts thereof. Class V antiarrhythmicsinclude, but are not limited to, digoxin and adenosine, andpharmaceutically acceptable salts thereof.

The present invention also includes derivatives of the aboveantiarrhythmic pharmaceutical agents such as solvates, salts, solvatedsalts, esters, amides, hydrazides, N-alkyls, and/or N-amino acyls. Thederivatives of the antiarrhythmic pharmaceutical agents can bepharmaceutically acceptable derivatives. Examples of ester derivativesinclude, but are not limited to, methyl esters, choline esters, anddimethylaminopropyl esters. Examples of amide derivatives include, butare not limited to, primary, secondary, and tertiary amides. Examples ofhydrazide derivatives include, but are not limited to,N-methylpiperazine hydrazides. Examples of N-alkyl derivatives include,but are not limited to, N′,N′,N′-trimethyl and N′,N′-dimethylaminopropylsuccininimidyl derivatives of antiarrhythmic pharmaceutical agent methylesters. Examples of N-aminoacyl derivatives include, but are not limitedto, N-ornithyl-, N-diaminopropionyl-, N-lysil-, N-hexamethyllysil-, andN-piperdine-propionyl- orN′,N′-methyl-1-piperazine-propionyl-antiarrhythmic pharmaceutical agentmethyl esters.

The antiarrhythmic pharmaceutical agents may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers, and/ordiastereomers. All such single stereoisomers, racemates, and mixturesthereof are intended to be within the scope of the present invention.These various forms of the compounds may be isolated/prepared by methodsknown in the art.

The antiarrhythmic pharmaceutical agents of the present invention may beprepared in a racemic mixture (e.g., mixture of isomers) that containsmore than 50%, preferably at least 75%, and more preferably at least 90%of the desired isomer (e.g., 80% enantiomeric or diastereomeric excess).According to particularly preferred embodiments, the compounds of thepresent invention are prepared in a form that contains at least 95% (90%e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.),and most preferably at least 99% (98% e.e. or d.e.) of the desiredisomer. Compounds identified herein as single stereoisomers are meant todescribe compounds used in a form that contains more than 50% of asingle isomer. By using known techniques, these compounds may beisolated in any of such forms by slightly varying the method ofpurification and/or isolation from the solvents used in the syntheticpreparation of such compounds.

The pharmaceutical composition according to one or more embodiments ofthe invention may comprise one or more antiarrhythmic pharmaceuticalagents and, optionally, one or more other active ingredients and,optionally, one or more pharmaceutically acceptable excipients. Forexample, the pharmaceutical composition may comprise neat particles ofantiarrhythmic pharmaceutical agent (e.g., particles containing only theantiarrhythmic pharmaceutical agent), may comprise neat particles ofantiarrhythmic pharmaceutical agent together with other particles,and/or may comprise particles comprising antiarrhythmic pharmaceuticalagent and one or more active ingredients and/or one or morepharmaceutically acceptable excipients.

Thus, the pharmaceutical composition according to one or moreembodiments of the invention may, if desired, contain a combination ofantiarrhythmic pharmaceutical agent and one or more additional activeagents. Examples of additional active agents include, but are notlimited to, agents that may be delivered through the lungs.

Additional active agents may comprise, for example, hypnotics andsedatives, psychic energizers, tranquilizers, respiratory drugs,anticonvulsants, muscle relaxants, antiparkinson agents (dopamineantagnonists), analgesics, anti-inflammatories, antianxiety drugs(anxiolytics), appetite suppressants, antimigraine agents, musclecontractants, additional anti-infectives (antivirals, antifungals,vaccines) antiarthritics, antimalarials, antiemetics, anepileptics,cytokines, growth factors, anti-cancer agents, antithrombotic agents,antihypertensives, cardiovascular drugs, antiarrhythmics, antioxidants,anti-asthma agents, hormonal agents including contraceptives,sympathomimetics, diuretics, lipid regulating agents, antiandrogenicagents, antiparasitics, anticoagulants, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,antienteritis agents, vaccines, antibodies, diagnostic agents, andcontrasting agents. The additional active agent, when administered byinhalation, may act locally or systemically.

The additional active agent may fall into one of a number of structuralclasses, including but not limited to small molecules, peptides,polypeptides, proteins, polysaccharides, steroids, proteins capable ofeliciting physiological effects, nucleotides, oligonucleotides,polynucleotides, fats, electrolytes, and the like.

Examples of additional active agents suitable for use in this inventioninclude but are not limited to one or more of calcitonin, amphotericinB, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme,cyclosporin, granulocyte colony stimulating factor (GCSF),thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin,granulocyte macrophage colony stimulating factor (GMCSF), growthhormone, human growth hormone (HGH), growth hormone releasing hormone(GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha,interferon beta, interferon gamma, interleukin-1 receptor,interleukin-2, interleukin-1 receptor antagonist, interleukin-3,interleukin-4, interleukin-6, luteinizing hormone releasing hormone(LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g.,mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which isincorporated herein by reference in its entirety), amylin, C-peptide,somatostatin, somatostatin analogs including octreotide, vasopressin,follicle stimulating hormone (FSH), insulin-like growth factor (IGF),insulintropin, macrophage colony stimulating factor (M-CSF), nervegrowth factor (NGF), tissue growth factors, keratinocyte growth factor(KGF), glial growth factor (GGF), tumor necrosis factor (TNF),endothelial growth factors, parathyroid hormone (PTH), glucagon-likepeptide thymosin alpha 1, IIb/IIa inhibitor, alpha-1 antitrypsin,phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates,respiratory syncytial virus antibody, cystic fibrosis transmembraneregulator (CFFR) gene, deoxyribonuclease (DNase),bactericidal/permeability increasing protein (BPI), anti-CMV antibody,13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin,clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin,josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin,andazithromycin, and swinolide A; fluoroquinolones such asciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin,moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin,lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin,fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,clinafloxacin, and sitafloxacin, teicoplanin, rampolanin, mideplanin,colistin, daptomycin, gramicidin, colistimethate, polymixins such aspolymixin B, capreomycin, bacitracin, penems; penicillins includingpenicllinase-sensitive agents like penicillin G, penicillin V,penicillinase-resistant agents like methicillin, oxacillin, cloxacillin,dicloxacillin, floxacillin, nafcillin; gram negative microorganismactive agents like ampicillin, amoxicillin, and hetacillin, cillin, andgalampicillin; antipseudomonal penicillins like carbenicillin,ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporinslike cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone,cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin,cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil,cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine,cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan,cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams likeaztreonam; and carbapenems such as imipenem, meropenem, pentamidineisethiouate, lidocaine, metaproterenol sulfate, beclomethasonediprepionate, triamcinolone acetamide, budesonide acetonide,fluticasone, ipratropium bromide, flunisolide, cromolyn sodium,ergotamine tartrate and where applicable, analogues, agonists,antagonists, inhibitors, and pharmaceutically acceptable salt forms ofthe above. In reference to peptides and proteins, the invention isintended to encompass synthetic, native, glycosylated, unglycosylated,pegylated forms, and biologically active fragments, derivatives, andanalogs thereof.

Additional active agents for use in the invention can further includenucleic acids, as bare nucleic acid molecules, vectors, associated viralparticles, plasmid DNA or RNA or other nucleic acid constructions of atype suitable for transfection or transformation of cells, e.g.,suitable for gene therapy including antisense. Further, an active agentmay comprise live attenuated or killed viruses suitable for use asvaccines. Other useful drugs include those listed within the Physician'sDesk Reference (most recent edition), which is incorporated herein byreference in its entirety.

When a combination of active agents is used, the agents may be providedin combination in a single species of pharmaceutical composition orindividually in separate species of pharmaceutical compositions.

The amount of antiarrhythmic pharmaceutical agent in the pharmaceuticalcomposition may vary. The amount of antiarrhythmic pharmaceuticalagent(s) is typically at least about 5 wt %, such as at least about 10wt %, at least about 20 wt %, at least about 30 wt %, at least about 40wt %, at least about 50 wt %, at least about 60 wt %, at least about 70wt %, or at least about 80 wt %, of the total amount of thepharmaceutical composition. The amount of antiarrhythmic pharmaceuticalagent(s) generally varies between about 0.1 wt % to 100 wt %, such asabout 5 wt % to about 95 wt %, about 10 wt % to about 90 wt %, about 30wt % to about 80 wt %, about 40 wt % to about 70 wt %, or about 50 wt %to about 60 wt %.

As noted above, the pharmaceutical composition may include one or morepharmaceutically acceptable excipient. Examples of pharmaceuticallyacceptable excipients include, but are not limited to, lipids, metalions, surfactants, amino acids, carbohydrates, buffers, salts, polymers,and the like, and combinations thereof.

Examples of lipids include, but are not limited to, phospholipids,glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid,cardiolipin; lipids bearing polymer chains such as polyethylene glycol,chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearingsulfonated mono-, di-, and polysaccharides; fatty acids such as palmiticacid, stearic acid, and oleic acid; cholesterol, cholesterol esters, andcholesterol hemisuccinate.

In one or more embodiments, the phospholipid comprises a saturatedphospholipid, such as one or more phosphatidylcholines. Exemplary acylchain lengths are 16:0 and 18:0 (e.g., palmitoyl and stearoyl). Thephospholipid content may be determined by the active agent activity, themode of delivery, and other factors.

Phospholipids from both natural and synthetic sources may be used invarying amounts. When phospholipids are present, the amount is typicallysufficient to coat the active agent(s) with at least a single molecularlayer of phospholipid. In general, the phospholipid content ranges fromabout 5 wt % to about 99.9 wt %, such as about 20 wt % to about 80 wt %.

Generally, compatible phospholipids can comprise those that have a gelto liquid crystal phase transition greater than about 40° C., such asgreater than about 60° C., or greater than about 80° C. The incorporatedphospholipids may be relatively long chain (e.g., C₁₆-C₂₂) saturatedlipids. Exemplary phospholipids useful in the present invention include,but are not limited to, phosphoglycerides such asdipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine,diphosphatidyl glycerols, short-chain phosphatidylcholines, hydrogenatedphosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen,Germany), long-chain saturated phosphatidylethanolamines, long-chainsaturated phosphatidylserines, long-chain saturatedphosphatidylglycerols, long-chain saturated phosphatidylinositols,phosphatidic acid, phosphatidylinositol, and sphingomyelin.

Examples of metal ions include, but are not limited to, divalentcations, including calcium, magnesium, zinc, iron, and the like. Forinstance, when phospholipids are used, the pharmaceutical compositionmay also comprise a polyvalent cation, as disclosed in WO 01/85136 andWO 01/85137, which are incorporated herein by reference in theirentireties. The polyvalent cation may be present in an amount effectiveto increase the melting temperature (T_(m)) of the phospholipid suchthat the pharmaceutical composition exhibits a T_(m) which is greaterthan its storage temperature (T_(m)) by at least about 20° C., such asat least about 40° C. The molar ratio of polyvalent cation tophospholipid may be at least about 0.05:1, such as about 0.05:1 to about2.0:1 or about 0.25:1 to about 1.0:1. An example of the molar ratio ofpolyvalent cation:phospholipid is about 0.50:1. When the polyvalentcation is calcium, it may be in the form of calcium chloride. Althoughmetal ion, such as calcium, is often included with phospholipid, none isrequired.

As noted above, the pharmaceutical composition may include one or moresurfactants. For instance, one or more surfactants may be in the liquidphase with one or more being associated with solid particles orparticles of the composition. By “associated with” it is meant that thepharmaceutical compositions may incorporate, adsorb, absorb, be coatedwith, or be formed by the surfactant. Surfactants include, but are notlimited to, fluorinated and nonfluorinated compounds, such as saturatedand unsaturated lipids, nonionic detergents, nonionic block copolymers,ionic surfactants, and combinations thereof. It should be emphasizedthat, in addition to the aforementioned surfactants, suitablefluorinated surfactants are compatible with the teachings herein and maybe used to provide the desired preparations.

Examples of nonionic detergents include, but are not limited to,sorbitan esters including sorbitan trioleate (Span™ 85), sorbitansesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene(20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate,oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether,lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters.Other suitable nonionic detergents can be easily identified usingMcCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock,N.J.), which is incorporated herein by reference in its entirety.

Examples of block copolymers include, but are not limited to, diblockand triblock copolymers of polyoxyethylene and polyoxypropylene,including poloxamer 188 (Pluronic™ F-68), poloxamer 407 (Pluronic™F-127), and poloxamer 338.

Examples of ionic surfactants include, but are not limited to, sodiumsulfosuccinate, and fatty acid soaps.

Examples of amino acids include, but are not limited to hydrophobicamino acids. Use of amino acids as pharmaceutically acceptableexcipients is known in the art as disclosed in WO 95/31479, WO 96/32096,and WO 96/32149, which are incorporated herein by reference in theirentireties.

Examples of carbohydrates include, but are not limited to,monosaccharides, disaccharides, and polysaccharides. For example,monosaccharides such as dextrose (anhydrous and monohydrate), galactose,mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides suchas lactose, maltose, sucrose, trehalose, and the like; trisaccharidessuch as raffinose and the like; and other carbohydrates such as starches(hydroxyethylstarch), cyclodextrins, and maltodextrins.

Examples of buffers include, but are not limited to, tris or citrate.

Examples of acids include, but are not limited to, carboxylic acids.

Examples of salts include, but are not limited to, sodium chloride,salts of carboxylic acids, (e.g., sodium citrate, sodium ascorbate,magnesium gluconate, sodium gluconate, tromethamine hydrochloride,etc.), ammonium carbonate, ammonium acetate, ammonium chloride, and thelike.

Examples of organic solids include, but are not limited to, camphor, andthe like.

The pharmaceutical composition of one or more embodiments of the presentinvention may also include a biocompatible, such as biodegradablepolymer, copolymer, or blend or other combination thereof. In thisrespect useful polymers comprise polylactides, polylactide-glycolides,cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose,polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones,polysaccharides (dextrans, starches, chitin, chitosan, etc.), hyaluronicacid, proteins, (albumin, collagen, gelatin, etc.). Those skilled in theart will appreciate that, by selecting the appropriate polymers, thedelivery efficiency of the composition and/or the stability of thedispersions may be tailored to optimize the effectiveness of theantiarrhythmic pharmaceutical agent(s).

For solutions, the compositions may include one or more osmolalityadjuster, such as sodium chloride. For instance, sodium chloride may beadded to solutions to adjust the osmolality of the solution. In one ormore embodiments, an aqueous composition consists essentially of theantiarrhythmic pharmaceutical agent, the osmolality adjuster, and water.

Solutions may also comprise a buffer or a pH adjusting agent, typicallya salt prepared from an organic acid or base. Representative bufferscomprise organic acid salts of citric acid, lactic acid, ascorbic acid,gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid,or phthalic acid, Tris, tromethamine hydrochloride, or phosphatebuffers. Thus, the buffers include citrates, phosphates, phthalates, andlactates.

Besides the above mentioned pharmaceutically acceptable excipients, itmay be desirable to add other pharmaceutically acceptable excipients tothe pharmaceutical composition to improve particle rigidity, productionyield, emitted dose and deposition, shelf-life, and patient acceptance.Such optional pharmaceutically acceptable excipients include, but arenot limited to: coloring agents, taste masking agents, buffers,hygroscopic agents, antioxidants, and chemical stabilizers. Further,various pharmaceutically acceptable excipients may be used to providestructure and form to the particle compositions (e.g., latex particles).In this regard, it will be appreciated that the rigidifying componentscan be removed using a post-production technique such as selectivesolvent extraction.

The pharmaceutical compositions of one or more embodiments of thepresent invention can lack taste. In this regard, although taste maskingagents are optionally included within the composition, the compositionsoften do not include a taste masking agent and lack taste even without ataste masking agent.

The pharmaceutical compositions may also include mixtures ofpharmaceutically acceptable excipients. For instance, mixtures ofcarbohydrates and amino acids are within the scope of the presentinvention.

The compositions of one or more embodiments of the present invention maytake various forms, such as solutions, dry powders, reconstitutedpowders, suspensions, or dispersions comprising a non-aqueous phase,such as propellants (e.g., chlorofluorocarbon, hydrofluoroalkane).

The solutions of the present invention are typically clear. In thisregard, many of the antiarrhythmic pharmaceutical agents of the presentinvention are water soluble.

In some embodiments, the isotonicity of the solution ranges fromisotonic to physiologic isotonicity. Physiologic isotonicity is theisotonicity of physiological fluids.

The compositions typically have a pH ranging from 3.5 to 8.0, such asfrom 4.0 to 7.5, or 4.5 to 7.0, or 5.0 to 6.5.

For dry powders, the moisture content is typically less than about 15 wt%, such as less than about 10 wt %, less than about 5 wt %, less thanabout 2 wt %, less than about 1 wt %, or less than about 0.5 wt %. Suchpowders are described in WO 95/24183, WO 96/32149, WO 99/16419, WO99/16420, and WO 99/16422, which are incorporated herein by reference intheir entireties.

In one version, the pharmaceutical composition comprises antiarrhythmicpharmaceutical agent incorporated into a phospholipid matrix. Thepharmaceutical composition may comprise phospholipid matrices thatincorporate the active agent and that are in the form of particles thatare hollow and/or porous microstructures, as described in theaforementioned WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, andWO 01/85137, which are incorporated herein by reference in theirentireties. The hollow and/or porous microstructures are useful indelivering the antiarrhythmic pharmaceutical agent to the lungs becausethe density, size, and aerodynamic qualities of the hollow and/or porousmicrostructures facilitate transport into the deep lungs during a user'sinhalation. In addition, the phospholipid-based hollow and/or porousmicrostructures reduce the attraction forces between particles, makingthe pharmaceutical composition easier to deagglomerate duringaerosolization and improving the flow properties of the pharmaceuticalcomposition making it easier to process.

In one version, the pharmaceutical composition is composed of hollowand/or porous microstructures having a bulk density less than about 1.0g/cm³, less than about 0.5 g/cm³, less than about 0.3 g/cm³, less thanabout 0.2 g/cm³, or less than about 0.1 g/cm³. By providing low bulkdensity particles or particles, the minimum powder mass that can befilled into a unit dose container is reduced, which eliminates the needfor carrier particles. That is, the relatively low density of thepowders of one or more embodiments of the present invention provides forthe reproducible administration of relatively low dose pharmaceuticalcompounds. Moreover, the elimination of carrier particles willpotentially reduce throat deposition and any “gag” effect or coughing,since large carrier particles, e.g., lactose particles, will impact thethroat and upper airways due to their size.

In some aspects, the present invention involves high rugosity particles.For instance, the particles may have a rugosity of greater than 2, suchas greater than 3, or greater than 4, and the rugosity may range from 2to 15, such as 3 to 10.

In one version, the pharmaceutical composition is in dry powder form andis contained within a unit dose receptacle which may be inserted into ornear the aerosolization apparatus to aerosolize the unit dose of thepharmaceutical composition. This version is useful in that the drypowder form may be stably stored in its unit dose receptacle for a longperiod of time. In some examples, pharmaceutical compositions of one ormore embodiments of the present invention may be stable for at least 2years. In some versions, no refrigeration is required to obtainstability. In other versions, reduced temperatures, e.g., at 2-8° C.,may be used to prolong stable storage. In many versions, the storagestability allows aerosolization with an external power source.

It will be appreciated that the pharmaceutical compositions disclosedherein may comprise a structural matrix that exhibits, defines orcomprises voids, pores, defects, hollows, spaces, interstitial spaces,apertures, perforations or holes. The absolute shape (as opposed to themorphology) of the perforated microstructure is generally not criticaland any overall configuration that provides the desired characteristicsis contemplated as being within the scope of the invention. Accordingly,some embodiments comprise approximately spherical shapes. However,collapsed, deformed or fractured particles are also compatible.

In one version, the antiarrhythmic pharmaceutical agent is incorporatedin a matrix that forms a discrete particle, and the pharmaceuticalcomposition comprises a plurality of the discrete particles. Thediscrete particles may be sized so that they are effectivelyadministered and/or so that they are available where needed. Forexample, for an aerosolizable pharmaceutical composition, the particlesare of a size that allows the particles to be aerosolized and deliveredto a user's respiratory tract during the user's inhalation.

The matrix material may comprise a hydrophobic or a partiallyhydrophobic material. For example, the matrix material may comprise alipid, such as a phospholipid, and/or a hydrophobic amino acid, such asleucine or tri-leucine. Examples of phospholipid matrices are describedin WO 99/16419, WO 99/16420, WO 99/16422, WO 01/85136, and WO 01/85137and in U.S. Pat. Nos. 5,874,064; 5,855,913; 5,985,309; 6,503,480; and7,473,433, and in U.S. Published App. No. 20040156792, all of which areincorporated herein by reference in their entireties. Examples ofhydrophobic amino acid matrices are described in U.S. Pat. Nos.6,372,258; 6,358,530; and 7,473,433, which are incorporated herein byreference in their entireties.

When phospholipids are utilized as the matrix material, thepharmaceutical composition may also comprise a polyvalent cation, asdisclosed in WO 01/85136 and WO 01/85137, which are incorporated hereinby reference in their entireties.

According to another embodiment, release kinetics of the compositioncontaining antiarrhythmic pharmaceutical agent(s) is controlled.According to one or more embodiments, the compositions of the presentinvention provide immediate release of the antiarrhythmic pharmaceuticalagent(s). Alternatively, the compositions of other embodiments of thepresent invention may be provided as non-homogeneous mixtures of activeagent incorporated into a matrix material and unincorporated activeagent in order to provide desirable release rates of antiarrhythmicpharmaceutical agent According to this embodiment, antiarrhythmicpharmaceutical agents formulated using the emulsion-based manufacturingprocess of one or more embodiments of the present invention have utilityin immediate release applications when administered to the respiratorytract. Rapid release is facilitated by: (a) the high specific surfacearea of the low density porous powders; (b) the small size of the drugcrystals that are incorporated therein, and; (c) the low surface energyof the particles.

Alternatively, it may be desirable to engineer the particle matrix sothat extended release of the active agent(s) is effected. This may beparticularly desirable when the active agent(s) is rapidly cleared fromthe lungs or when sustained release is desired. For example, the natureof the phase behavior of phospholipid molecules is influenced by thenature of their chemical structure and/or preparation methods inspray-drying feedstock and drying conditions and other compositioncomponents utilized. In the case of spray-drying of active agent(s)solubilized within a small unilamellar vesicle (SUV) or multilamellarvesicle (MLV), the active agent(s) are encapsulated within multiplebilayers and are released over an extended time.

In contrast, spray-drying of a feedstock comprised of emulsion dropletsand dispersed or dissolved active agent(s) in accordance with theteachings herein leads to a phospholipid matrix with less long-rangeorder, thereby facilitating rapid release. While not being bound to anyparticular theory, it is believed that this is due in part to the factthat the active agent(s) are never formally encapsulated in thephospholipid, and the fact that the phospholipid is initially present onthe surface of the emulsion droplets as a monolayer (not a bilayer as inthe case of liposomes). The spray-dried particles prepared by theemulsion-based manufacturing process of one or more embodiments of thepresent invention often have a high degree of disorder. Also, thespray-dried particles typically have low surface energies, where valuesas low as 20 mN/m have been observed for spray-dried DSPC particles(determined by inverse gas chromatography). Small angle X-ray scattering(SAXS) studies conducted with spray-dried phospholipid particles havealso shown a high degree of disorder for the lipid, with scatteringpeaks smeared out, and length scales extending in some instances onlybeyond a few nearest neighbors.

It should be noted that a matrix having a high gel to liquid crystalphase transition temperature is not sufficient in itself to achievesustained release of the active agent(s). Having sufficient order forthe bilayer structures is also important for achieving sustainedrelease. To facilitate rapid release, an emulsion-system of highporosity (high surface area), and minimal interaction between the drugsubstance and phospholipid may be used. The pharmaceutical compositionformation process may also include the additions of other compositioncomponents (e.g., small polymers such as Pluronic F-68; carbohydrates,salts, hydrotropes) to break the bilayer structure are alsocontemplated.

To achieve a sustained release, incorporation of the phospholipid inbilayer form may be used, especially if the active agent is encapsulatedtherein. In this case increasing the T_(m) of the phospholipid mayprovide benefit via incorporation of divalent counterions orcholesterol. As well, increasing the interaction between thephospholipid and drug substance via the formation of ion-pairs(negatively charged active+steaylamine, positively chargedactive+phosphatidylglycerol) would tend to decrease the dissolutionrate. If the active is amphiphilic, surfactant/surfactant interactionsmay also slow active dissolution.

The addition of divalent counterions (e.g., calcium or magnesium ions)to long-chain saturated phosphatidylcholines results in an interactionbetween the negatively charged phosphate portion of the zwitterionicheadgroup and the positively charged metal ion. This results in adisplacement of water of hydration and a condensation of the packing ofthe phospholipid lipid headgroup and acyl chains. Further, this resultsin an increase in the Tm of the phospholipid. The decrease in headgrouphydration can have profound effects on the spreading properties ofspray-dried phospholipid particles on contact with water. A fullyhydrated phosphatidylcholine molecule will diffuse very slowly to adispersed crystal via molecular diffusion through the water phase. Theprocess is exceedingly slow because the solubility of the phospholipidin water is very low (about 10⁻¹⁰ mol/L for DPPC). Prior art attempts toovercome this phenomenon include homogenizing the crystals in thepresence of the phospholipid. In this case, the high degree of shear andradius of curvature of the homogenized crystals facilitates coating ofthe phospholipid on the crystals. In contrast, “dry” phospholipidpowders according to one or more embodiments of this invention canspread rapidly when contacted with an aqueous phase, thereby coatingdispersed crystals without the need to apply high energies.

For example, upon reconstitution, the surface tension of spray-driedDSPC/Ca mixtures at the air/water interface decreases to equilibriumvalues (about 20 mN/m) as fast as a measurement can be taken. Incontrast, liposomes of DSPC decrease the surface tension (about 50 mN/m)very little over a period of hours, and it is likely that this reductionis due to the presence of hydrolysis degradation products such as freefatty acids in the phospholipid. Single-tailed fatty acids can diffusemuch more rapidly to the air/water interface than can the hydrophobicparent compound. Hence, the addition of calcium ions tophosphatidylcholines can facilitate the rapid encapsulation ofcrystalline drugs more rapidly and with lower applied energy.

In another version, the pharmaceutical composition comprises low densityparticles achieved by co-spray-drying nanocrystals with aperfluorocarbon-in-water emulsion. The nanocrystals may be formed byprecipitation and may, e.g., range in size from about 45 μm to about 80μm. Examples of perfluorocarbons include, but are not limited to,perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane,perfluorodecalin, perfluorobutyl ethane.

In accordance with the teachings herein the particles may be provided ina “dry” state. That is, in one or more embodiments, the particles willpossess a moisture content that allows the powder to remain chemicallyand physically stable during storage at ambient or reduced temperatureand remain dispersible. In this regard, there is little or no change inprimary particle size, content, purity, and aerodynamic particle sizedistribution.

As such, the moisture content of the particles is typically less thanabout 10 wt %, such as less than about 6 wt %, less than about 3 wt %,or less than about 1 wt %. The moisture content is, at least in part,dictated by the composition and is controlled by the process conditionsemployed, e.g., inlet temperature, feed concentration, pump rate, andblowing agent type, concentration and post drying. Reduction in boundwater leads to significant improvements in the dispersibility andflowability of phospholipid based powders, leading to the potential forhighly efficient delivery of powdered lung surfactants or particlecomposition comprising active agent dispersed in the phospholipid. Theimproved dispersibility allows simple passive DPI devices to be used toeffectively deliver these powders.

Yet another version of the pharmaceutical composition includes particlecompositions that may comprise, or may be partially or completely coatedwith, charged species that prolong residence time at the point ofcontact or enhance penetration through mucosae. For example, anioniccharges are known to favor mucoadhesion while cationic charges may beused to associate the formed particle with negatively charged bioactiveagents such as genetic material. The charges may be imparted through theassociation or incorporation of polyanionic or polycationic materialssuch as polyacrylic acids, polylysine, polylactic acid, and chitosan.

In some versions, the pharmaceutical composition comprises particleshaving a mass median diameter less than about 20 μm, such as less thanabout 10 μm, less than about 7 μm, or less than about 5 μm. Theparticles may have a mass median aerodynamic diameter ranging from about1 μm to about 6 μm, such as about 1.5 μm to about 5 μm, or about 2 μm toabout 4 μm. If the particles are too large, a larger percentage of theparticles may not reach the lungs. If the particles are too small, alarger percentage of the particles may be exhaled.

Unit doses of the pharmaceutical compositions may be placed in acontainer. Examples of containers include, but are not limited to,syringes, capsules, blow fill seal, blisters, vials, ampoules, orcontainer closure systems made of metal, polymer (e.g., plastic,elastomer), glass, or the like. For instance, the vial may be acolorless Type I borosilicate glass ISO 6R 10 mL vial with a chlorobutylrubber siliconized stopper, and rip-off type aluminum cap with coloredplastic cover.

The container may be inserted into an aerosolization device. Thecontainer may be of a suitable shape, size, and material to contain thepharmaceutical composition and to provide the pharmaceutical compositionin a usable condition. For example, the capsule or blister may comprisea wall which comprises a material that does not adversely react with thepharmaceutical composition. In addition, the wall may comprise amaterial that allows the capsule to be opened to allow thepharmaceutical composition to be aerosolized. In one version, the wallcomprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC),polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar,aluminum foil, or the like. In one version, the capsule may comprisetelescopically adjoining sections, as described for example in U.S. Pat.No. 4,247,066 which is incorporated herein by reference in its entirety.The size of the capsule may be selected to adequately contain the doseof the pharmaceutical composition. The sizes generally range from size 5to size 000 with the outer diameters ranging from about 4.91 mm to 9.97mm, the heights ranging from about 11.10 mm to about 26.14 mm, and thevolumes ranging from about 0.13 mL to about 1.37 mL, respectively.Suitable capsules are available commercially from, for example, ShionogiQualicaps Co. in Nara, Japan and Capsugel in Greenwood, S.C. Afterfilling, a top portion may be placed over the bottom portion to form acapsule shape and to contain the powder within the capsule, as describedin U.S. Pat. Nos. 4,846,876 and 6,357,490, and in WO 00/07572, which areincorporated herein by reference in their entireties. After the topportion is placed over the bottom portion, the capsule can optionally bebanded.

For solutions, the amount of the composition in the unit dose typicallyranges from about 0.5 ml to about 15 ml, such as about 2 ml to about 15ml, from about 3 ml to about 10 ml, about 4 ml to about 8 ml, or about 5ml to about 6 ml.

The compositions of the present invention may be made by any of thevarious methods and techniques known and available to those skilled inthe art.

For instance, a solution of antiarrhythmic pharmaceutical agent may bemade using the following procedure. Typically, manufacturing equipmentis sterilized before use. A portion of the final volume, e.g., 70%, ofsolvent, e.g., water for injection, may be added into a suitablecontainer. Antiarrhythmic pharmaceutical agent may then be added. Theantiarrhythmic pharmaceutical agent may be mixed until dissolved.Additional solvent may be added to make up the final batch volume. Thebatch may be filtered, e.g., through a 0.2 μm filter into a sterilizedreceiving vessel. Filling components may be sterilized before use infilling the batch into vials, e.g., 10 ml vials.

As an example, the above-noted sterilizing may include the following. A5 liter type 1 glass bottle and lid may be placed in an autoclave bagand sterilized at elevated temperature, e.g., 121° C. for 15 minutes,using an autoclave. Similarly, vials may be placed into suitable racks,inserted into an autoclave bag, and sterilized at elevated temperature,e.g., 121° C. for 15 minutes, using an autoclave. Also similarly,stoppers may be placed in an autoclave bag and sterilized at elevatedtemperature, e.g., 121° C. for 15 minutes, using an autoclave. Beforesterilization, sterilizing filters may be attached to tubing, e.g., a 2mm length of 7 mm×13 mm silicone tubing. A filling line may be preparedby placed in an autoclave bag and sterilized at elevated temperature,e.g., 121° C. for 15 minutes, using an autoclave.

The above-noted filtration may involve filtration into a laminar flowwork area. The receiving bottle and filters may be set up in the laminarflow work area.

The above-noted filling may also be conducted under laminar flowprotection. The filling line may be unwrapped and placed into thereceiving bottle. The sterilized vials and stoppers may be unwrappedunder laminar flow protection. Each vial may be filled, e.g., to atarget fill of 5 g, and stoppered. A flip off collar may be applied toeach vial. The sealed vials may be inspected for vial leakage, correctoverseals, and cracks.

In certain cases, the antiarrhythmic pharmaceutical agent may be in asolution. In particular examples, the solution is an aqueous solution.In other examples, the antiarrhythmic pharmaceutical agent can bepresent at a concentration from about 1 mg/mL to about 60 mg/mL, such as1 mg/mL to 5 mg/mL, 1 mg/ml to 10 mg/mL, 1 mg/ml to 15 mg/mL, 1 mg/mL to20 mg/mL, 1 mg/mL to 25 mg/mL, 1 mg/mL to 30 mg/mL, 1 mg/mL to 35 mg/mL,1 mg/mL to 40 mg/mL, 1 mg/mL to 45 mg/mL, 1 mg/mL to 50 mg/mL, 1 mg/mLto 55 mg/mL, 5 mg/ml to 10 mg/mL, 5 mg/ml to 15 mg/mL, 5 mg/mL to 20mg/mL, 5 mg/mL to 25 mg/mL, 5 mg/mL to 30 mg/mL, 5 mg/mL to 35 mg/mL, 5mg/mL to 40 mg/mL, 5 mg/mL to 45 mg/mL, 5 mg/mL to 50 mg/mL, 5 mg/mL to55 mg/mL, 5 mg/mL to 60 mg/mL; 10 mg/ml to 15 mg/mL, 10 mg/mL to 20mg/mL, 10 mg/mL to 25 mg/mL, 10 mg/mL to 30 mg/mL, 10 mg/mL to 35 mg/mL,10 mg/mL to 40 mg/mL, 10 mg/mL to 45 mg/mL, 10 mg/mL to 50 mg/mL, 10mg/mL to 55 mg/mL, 10 mg/mL to 60 mg/mL, 15 mg/mL to 20 mg/mL, 15 mg/mLto 25 mg/mL, 15 mg/mL to 30 mg/mL, 15 mg/mL to 35 mg/mL, 15 mg/mL to 40mg/mL, 15 mg/mL to 45 mg/mL, 15 mg/mL to 50 mg/mL, 15 mg/mL to 55 mg/mL,15 mg/mL to 60 mg/mL, 20 mg/mL to 25 mg/mL, 20 mg/mL to 30 mg/mL, 20mg/mL to 35 mg/mL, 20 mg/mL to 40 mg/mL, 20 mg/mL to 45 mg/mL, 20 mg/mLto 50 mg/mL, 20 mg/mL to 55 mg/mL, 20 mg/mL to 60 mg/mL, 25 mg/mL to 30mg/mL, 25 mg/mL to 35 mg/mL, 25 mg/mL to 40 mg/mL, 25 mg/mL to 45 mg/mL,25 mg/mL to 50 mg/mL, 25 mg/mL to 55 mg/mL, 25 mg/mL to 60 mg/mL, 30mg/mL to 35 mg/mL, 30 mg/mL to 40 mg/mL, 30 mg/mL to 45 mg/mL, 30 mg/mLto 50 mg/mL, 30 mg/mL to 55 mg/mL, 30 mg/mL to 60 mg/mL, 35 mg/mL to 40mg/mL, 35 mg/mL to 45 mg/mL, 35 mg/mL to 50 mg/mL, 35 mg/mL to 55 mg/mL,35 mg/mL to 60 mg/mL, 40 mg/mL to 45 mg/mL, 40 mg/mL to 50 mg/mL, 40mg/mL to 55 mg/mL, 40 mg/mL to 60 mg/mL, 45 mg/mL to 50 mg/mL, 45 mg/mLto 55 mg/mL, 45 mg/mL to 60 mg/mL, 50 mg/mL to 55 mg/mL, 50 mg/mL to 60mg/mL, or 55 mg/mL to 60 mg/mL. In yet other embodiments, theantiarrhythmic pharmaceutical agent is be present at about 30 mg/mL, 31mg/mL, 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36 mg/mL, 37 mg/ml, 38mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL, 43 mg/mL, 44 mg/mL, 45mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50 mg/mL, 51 mg/mL, 52mg/mL, 53 mg/mL, 54 mg/mL, or 55 mg/mL.

As another example, an antiarrhythmic may be prepared by lyophilizingthe antiarrhythmic to form a powder for storage. The powder is thenreconstituted prior to use. This technique may be used when theantiarrhythmic is unstable in solution.

In some cases, the lyophilized powder can be reconstituted in a suitablesolvent such that the antiarrhythmic pharmaceutical agent is present ata concentration from about 1 mg/mL to about 60 mg/mL, such as 1 mg/mL to5 mg/mL, 1 mg/ml to 10 mg/mL, 1 mg/ml to 15 mg/mL, 1 mg/mL to 20 mg/mL,1 mg/mL to 25 mg/mL, 1 mg/mL to 30 mg/mL, 1 mg/mL to 35 mg/mL, 1 mg/mLto 40 mg/mL, 1 mg/mL to 45 mg/mL, 1 mg/mL to 50 mg/mL, 1 mg/mL to 55mg/mL, 5 mg/ml to 10 mg/mL, 5 mg/ml to 15 mg/mL, 5 mg/mL to 20 mg/mL, 5mg/mL to 25 mg/mL, 5 mg/mL to 30 mg/mL, 5 mg/mL to 35 mg/mL, 5 mg/mL to40 mg/mL, 5 mg/mL to 45 mg/mL, 5 mg/mL to 50 mg/mL, 5 mg/mL to 55 mg/mL,5 mg/mL to 60 mg/mL; 10 mg/ml to 15 mg/mL, 10 mg/mL to 20 mg/mL, 10mg/mL to 25 mg/mL, 10 mg/mL to 30 mg/mL, 10 mg/mL to 35 mg/mL, 10 mg/mLto 40 mg/mL, 10 mg/mL to 45 mg/mL, 10 mg/mL to 50 mg/mL, 10 mg/mL to 55mg/mL, 10 mg/mL to 60 mg/mL, 15 mg/mL to 20 mg/mL, 15 mg/mL to 25 mg/mL,15 mg/mL to 30 mg/mL, 15 mg/mL to 35 mg/mL, 15 mg/mL to 40 mg/mL, 15mg/mL to 45 mg/mL, 15 mg/mL to 50 mg/mL, 15 mg/mL to 55 mg/mL, 15 mg/mLto 60 mg/mL, 20 mg/mL to 25 mg/mL, 20 mg/mL to 30 mg/mL, 20 mg/mL to 35mg/mL, 20 mg/mL to 40 mg/mL, 20 mg/mL to 45 mg/mL, 20 mg/mL to 50 mg/mL,20 mg/mL to 55 mg/mL, 20 mg/mL to 60 mg/mL, 25 mg/mL to 30 mg/mL, 25mg/mL to 35 mg/mL, 25 mg/mL to 40 mg/mL, 25 mg/mL to 45 mg/mL, 25 mg/mLto 50 mg/mL, 25 mg/mL to 55 mg/mL, 25 mg/mL to 60 mg/mL, 30 mg/mL to 35mg/mL, 30 mg/mL to 40 mg/mL, 30 mg/mL to 45 mg/mL, 30 mg/mL to 50 mg/mL,30 mg/mL to 55 mg/mL, 30 mg/mL to 60 mg/mL, 35 mg/mL to 40 mg/mL, 35mg/mL to 45 mg/mL, 35 mg/mL to 50 mg/mL, 35 mg/mL to 55 mg/mL, 35 mg/mLto 60 mg/mL, 40 mg/mL to 45 mg/mL, 40 mg/mL to 50 mg/mL, 40 mg/mL to 55mg/mL, 40 mg/mL to 60 mg/mL, 45 mg/mL to 50 mg/mL, 45 mg/mL to 55 mg/mL,45 mg/mL to 60 mg/mL, 50 mg/mL to 55 mg/mL, 50 mg/mL to 60 mg/mL, or 55mg/mL to 60 mg/mL. In yet other embodiments, after reconstitution of alyophilized powder the antiarrhythmic pharmaceutical agent is present atabout 30 mg/mL, 31 mg/mL, 32 mg/mL, 33 mg/mL, 34 mg/mL, 35 mg/mL, 36mg/mL, 37 mg/ml, 38 mg/mL, 39 mg/mL, 40 mg/mL, 41 mg/mL, 42 mg/mL, 43mg/mL, 44 mg/mL, 45 mg/mL, 46 mg/mL, 47 mg/mL, 48 mg/mL, 49 mg/mL, 50mg/mL, 51 mg/mL, 52 mg/mL, 53 mg/mL, 54 mg/mL, or 55 mg/mL.

The solvent for the solution to be lyophilized may comprise water. Thesolution may be excipient-free. For instance, the solution may becryoprotectant-free.

In one or more embodiments, a suitable amount (e.g., 120 g per liter offinal solution) of drug substance may be dissolved, e.g., in about the75% of the theoretical total amount of water for injection undernitrogen bubbling. The dissolution time may be recorded and appearancemay be evaluated.

Then, the dilution to the final volume with WFI may be carried out.Final volume may be checked. Density, pH, endotoxin, bioburden, andcontent by UV may be measured both before and after sterile filtration.

The solution may be filtered before lyophilizing. For instance, a double0.22 μm filtration may be performed before filling. The filters may betested for integrity and bubble point before and after the filtration.

Pre-washed and autoclaved vials may be aseptically filled using anautomatic filling line to a target of 5 ml per vial and then partiallystoppered. In process check for fill volumes may be done by checking thefill weight every 15 minutes.

The lyophilizing is generally conducted within about 72 hours, such aswithin about 8 hours, or within about 4 hours, of the dissolving.

In one or more embodiments, the lyophilizing comprises freezing thesolution to form a frozen solution. The frozen solution is typicallyheld at an initial temperature ranging from about −40° C. to about −50°C., such as about −45° C. During the initial temperature period, thepressure around the frozen solution is typically atmospheric pressure.The initial temperature period typically ranges from about 1 hour toabout 4 hours, such about 1.5 hours to about 3 hours, or about 2 hours.

The lyophilizing may further comprise raising a temperature of thefrozen solution to a first predetermined temperature, which may rangefrom about 10° C. to about 20° C., such as about 15° C. The time for theheat ramp from the initial temperature to the first predeterminedtemperature generally ranges from about 6 hours to about 10 hours, suchas about 7 hours to about 9 hours.

During the first predetermined temperature period, the pressure aroundthe solution typically ranges from about 100 μbar to about 250 μbar,such as about 150 μbar to about 225 μbar. The solution may be held atthe first predetermined temperature for a period ranging from about 20hours to about 30 hours, such as from about 24 hours.

The lyophilizing may still further comprise raising a temperature of thesolution to a second predetermined temperature, which may range fromabout 25° C. to about 35° C., such as about 30° C. During the secondpredetermined temperature period, the pressure around the frozensolution typically ranges from about 100 μbar to about 250 μbar, such asabout 150 μbar to about 225 μbar. The solution may be held at the secondpredetermined temperature for a period ranging from about 10 hours toabout 20 hours.

In view of the above, the lyophilization cycle may comprise a freezingramp, e.g., from 20° C. to −45° C. in 65 minutes, followed by a freezesoak, e.g., at −45° C. for 2 hours. Primary drying may be accomplishedwith a heating ramp, e.g., from −45° C. to 15° C. in 8 hours, followedby a temperature hold, e.g., at 15° C. for 24 hours at a pressure of 200μbar. Secondary drying may be accomplished with a heating ramp, e.g.,from 15° C. to 30° C. in 15 minutes, followed by a temperature hold at30° C. for 15 hours at a pressure of 200 μbar. At the end of thelyophilization cycle, the vacuum may be broken with sterile nitrogen,and the vials may be automatically stoppered.

The water content of the lyophilized powder is typically less than about7 wt %, such as less than about 5 wt %, less than about 4 wt %, lessthan about 3 wt %, less than about 2 wt %, or less than about 1 wt %.

The powder is capable of being reconstituted with water at 25° C. and1.0 atmosphere and with manual agitation, in less than about 60 seconds,such as less than about 30 seconds, less than about 15 seconds, or lessthan about 10 seconds.

The powder typically has a large specific surface area that facilitatesreconstitution. The specific surface area typically ranges from about 5m²/g to about 20 m²/g, such as about 8 m²/g to 15 m²/g, or about 10 m²/gto 12 m²/g.

Upon reconstitution with water, the antiarrhythmic pharmaceutical agentsolution typically has a pH that ranges from about 2.5 to about 7, suchas about 3 to about 6.

For dry powders, the composition may be formed by spray drying,lyophilization, milling (e.g., wet milling, dry milling), and the like.

In spray drying, the preparation to be spray dried or feedstock can beany solution, coarse suspension, slurry, colloidal dispersion, or pastethat may be atomized using the selected spray drying apparatus. In thecase of insoluble agents, the feedstock may comprise a suspension asdescribed above. Alternatively, a dilute solution and/or one or moresolvents may be utilized in the feedstock. In one or more embodiments,the feed stock will comprise a colloidal system such as an emulsion,reverse emulsion microemulsion, multiple emulsion, particle dispersion,or slurry.

In one version, the antiarrhythmic pharmaceutical agent and the matrixmaterial are added to an aqueous feedstock to form a feedstock solution,suspension, or emulsion. The feedstock is then spray dried to producedried particles comprising the matrix material and the antiarrhythmicpharmaceutical agent. Suitable spray-drying processes are known in theart, for example as disclosed in WO 99/16419 and U.S. Pat. Nos.6,077,543; 6,051,256; 6,001,336; 5,985,248; and 5,976,574, which areincorporated herein by reference in their entireties.

Whatever components are selected, the first step in particle productiontypically comprises feedstock preparation. If a phospholipids-basedparticle is intended to act as a carrier for the antiarrhythmicpharmaceutical agent, the selected active agent(s) may be introducedinto a liquid, such as water, to produce a concentrated suspension. Theconcentration of antiarrhythmic pharmaceutical agent and optional activeagents typically depends on the amount of agent required in the finalpowder and the performance of the delivery device employed (e.g., thefine particle dose for a metered dose inhaler (MDI) or a dry powderinhaler (DPI)).

Any additional active agent(s) may be incorporated in a single feedstockpreparation and spray dried to provide a single pharmaceuticalcomposition species comprising a plurality of active agents. Conversely,individual active agents could be added to separate stocks and spraydried separately to provide a plurality of pharmaceutical compositionspecies with different compositions. These individual species could beadded to the suspension medium or dry powder dispensing compartment inany desired proportion and placed in the aerosol delivery system asdescribed below.

Polyvalent cation may be combined with the antiarrhythmic pharmaceuticalagent suspension, combined with the phospholipid emulsion, or combinedwith an oil-in-water emulsion formed in a separate vessel. Theantiarrhythmic pharmaceutical agent may also be dispersed directly inthe emulsion.

For example, polyvalent cation and phospholipid may be homogenized inhot distilled water (e.g., 70° C.) using a suitable high shearmechanical mixer (e.g., Ultra-Turrax model T-25 mixer) at 8000 rpm for 2to 5 min. Typically, 5 to 25 g of fluorocarbon is added dropwise to thedispersed surfactant solution while mixing. The resulting polyvalentcation-containing perfluorocarbon in water emulsion may then beprocessed using a high pressure homogenizer to reduce the particle size.Typically, the emulsion is processed for five discrete passes at 12,000to 18,000 PSI and kept at about 50° C. to about 80° C.

When the polyvalent cation is combined with an oil-in-water emulsion,the dispersion stability and dispersibility of the spray driedpharmaceutical composition can be improved by using a blowing agent, asdescribed in WO 99/16419, which is incorporated herein by reference inits entirety. This process forms an emulsion, optionally stabilized byan incorporated surfactant, typically comprising submicron droplets ofwater immiscible blowing agent dispersed in an aqueous continuous phase.The blowing agent may be a fluorinated compound (e.g., perfluorohexane,perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin,perfluorobutyl ethane) which vaporizes during the spray-drying process,leaving behind generally hollow, porous aerodynamically light particles.Other suitable liquid blowing agents include non-fluorinated oils,chloroform, Freon® fluorocarbons, ethyl acetate, alcohols, hydrocarbons,nitrogen, and carbon dioxide gases. The blowing agent may be emulsifiedwith a phospholipid.

Although the pharmaceutical compositions may be formed using a blowingagent as described above, it will be appreciated that, in someinstances, no additional blowing agent is required and an aqueousdispersion of the antiarrhythmic pharmaceutical agent and/orpharmaceutically acceptable excipients and surfactant(s) are spray drieddirectly. In such cases, the pharmaceutical composition may possesscertain physicochemical properties (e.g., high crystallinity, elevatedmelting temperature, surface activity, etc.) that make it particularlysuitable for use in such techniques.

As needed, cosurfactants such as poloxamer 188 or span 80 may bedispersed into this annex solution. Additionally, pharmaceuticallyacceptable excipients such as sugars and starches can also be added.

The feedstock(s) may then be fed into a spray dryer. Typically, thefeedstock is sprayed into a current of warm filtered air that evaporatesthe solvent and conveys the dried product to a collector. The spent airis then exhausted with the solvent. Commercial spray dryers manufacturedby Buchi Ltd. or Niro Corp. may be modified for use to produce thepharmaceutical composition. Examples of spray drying methods and systemssuitable for making the dry powders of one or more embodiments of thepresent invention are disclosed in U.S. Pat. Nos. 6,077,543; 6,051,256;6,001,336; 5,985,248; and 5,976,574, which are incorporated herein byreference in their entireties.

Operating conditions of the spray dryer such as inlet and outlettemperature, feed rate, atomization pressure, flow rate of the dryingair, and nozzle configuration can be adjusted in order to produce therequired particle size, and production yield of the resulting dryparticles. The selection of appropriate apparatus and processingconditions are within the purview of a skilled artisan in view of theteachings herein and may be accomplished without undue experimentation.Exemplary settings are as follows: an air inlet temperature betweenabout 60° C. and about 170° C.; an air outlet between about 40° C. toabout 120° C.; a feed rate between about 3 mL/min to about 15 mL/min; anaspiration air flow of about 300 L/min; and an atomization air flow ratebetween about 25/min and about 50 L/min. The settings will, of course,vary depending on the type of equipment used. In any event, the use ofthese and similar methods allow formation of aerodynamically lightparticles with diameters appropriate for aerosol deposition into thelung.

Hollow and/or porous microstructures may be formed by spray drying, asdisclosed in WO 99/16419, which is incorporated herein by reference. Thespray-drying process can result in the formation of a pharmaceuticalcomposition comprising particles having a relatively thin porous walldefining a large internal void. The spray-drying process is also oftenadvantageous over other processes in that the particles formed are lesslikely to rupture during processing or during deagglomeration.

Pharmaceutical compositions useful in one or more embodiments of thepresent invention may alternatively be formed by lyophilization.Lyophilization is a freeze-drying process in which water is sublimedfrom the composition after it is frozen. The lyophilization process isoften used because biologics and pharmaceuticals that are relativelyunstable in an aqueous solution may be dried without exposure toelevated temperatures, and then stored in a dry state where there arefewer stability problems. With respect to one or more embodiments of theinstant invention, such techniques are particularly compatible with theincorporation of peptides, proteins, genetic material and other naturaland synthetic macromolecules in pharmaceutical compositions withoutcompromising physiological activity. Lyophilized cake containing a finefoam-like structure can be micronized using techniques known in the artto provide particles of the desired size.

The compositions of one or more embodiments of the present invention maybe administered by inhalation.

Moreover, the doses of composition that are inhaled are typically muchless than those administered by other routes and required to obtainsimilar effects, due to the efficient targeting of the inhaledcomposition to the heart.

In one or more embodiments of the invention, a pharmaceuticalcomposition comprising antiarrhythmic pharmaceutical agent isadministered to the lungs of a patient in need thereof. For example, thepatient may have been diagnosed with an arrhythmia. Examples ofarrhythmias include, but are not limited to, tachycardia,supraventricular tachycardia (SVT), paroxysmal supraventriculartachycardia (PSVT), atrial fibrillation (AF), paroxysmal atrialfibrillation (PAF), persistent atrial fibrillation, permanent atrialfibrillation, atrial flutter, paroxysmal atrial flutter, and lone atrialfibrillation.

Thus, the pharmaceutical compositions of one or more embodiments of thepresent invention can be used to treat and/or provide prophylaxis for abroad range of patients. A suitable patient for, receiving treatmentand/or prophylaxis as described herein is any mammalian patient in needthereof, preferably such mammal is a human. Examples of patientsinclude, but are not limited to, pediatric patients, adult patients, andgeriatric patients. In some embodiments, the composition is intendedonly as a treatment for rapid resolution of symptoms and restoration ofnormal sinus rhythm, and is not taken as a preventative, e.g., when thepatient is well, there is no need for drug—this can increase thebenefit-risk ratio of the therapy and overall safety due to the sporadicor intermittent dosing, and the focus on reducing disabling symptoms andrestoring sinus rhythm only when needed.

The dosage necessary and the frequency of dosing of the antiarrhythmicpharmaceutical agent depend on the composition and concentration of theantiarrhythmic pharmaceutical agent within the composition. In somecases, the dose is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, or 95% of its normal intravenous dose. In some cases, the doseis about 5% to about 10%, is about 10% to about 20%, is about 20% toabout 30%, is about 30% to about 40%, is about 50% to about 60%, isabout 60% to about 70%, is about 70% to about 80%, is about 80% to about90%, or is about 90% to about 95% of the intravenous dose. The pulmonarydose is similar to intracardiac doses. Inhalation avoids dilution ofdrug in the body as compared to intravenous or oral dosing.

In some cases, the effective dosage administered intravenously can becalculated based on the weight of the subject. For example, in somecases, the effective dose administered intravenously to a subjectweighing 70 kg is 2 mg/kg (i.e., 140 mg).

Inhalation also avoids metabolism, such as hepatic metabolism. Forinstance, calcium channel blockers, such as diltiazem, undergosignificant hepatic metabolism when taken orally. Inhalation allowsrapid delivery of the parent diltiazem compound to the heart as a bolus.Surprisingly, administration by inhalation of diltiazem via theinhalation route according to the present invention converted atrialfibrillation to normal sinus rhythm and reduced heart rate. Thus,administration by inhalation of diltiazem can be useful for treatingboth atrial fibrillation and supraventricular tachycardia (SVT). Incontrast, administration by IV of diltiazem is typically only used forconverting SVT to normal sinus rhythm and in atrial fibrillation toreduce heart rate (not for converting to normal sinus rhythm).

Inhalation also avoids red blood cell metabolism. For instance, thereduced dilution and short route associated with inhalation reduces redblood cell metabolism of esmolol.

Inhalation may also avoid reduced blood pressure and fainting. Forinstance, IV administration of beta blockers, such as esmolol, mayreduce mean arterial blood pressure (MAP). Inhalation allows rapiddelivery of esmolol without reducing MAP. As a result, inhalation ofbeta blockers may result in an MAP of 10 mm Hg to 20 mm Hg greater thanthe MAP resulting from IV administration of the same beta blocker.

With inhaled cardiotherapy the drug is directed to the heart from thelungs as a bolus. So, the heart sees a high concentration. The drug israpidly diluted as it passes through the heart, but the exposure time issufficient for the desired pharmacological action. Once the drug passesthrough the heart, the concentration of the drug in the systemiccirculation (e.g., peripheral venous blood) is below the therapeuticconcentration and is considered ineffective. The therapeutic window isthe range of dosage of a drug or of its concentration in a bodily systemthat provides safe effective therapy. Anything below the minimum amountis sub-therapeutic and hence ineffective in that concentration. In viewof the dilution, unwanted side effects are minimized.

In one version, the antiarrhythmic may be administered daily. In thisversion, the daily dosage of antiarrhythmic pharmaceutical agent rangesfrom about 0.1 mg to about 600 mg, such as about 0.5 mg to about 500 mg,about 1 mg to about 400 mg, about 2 mg to about 300 mg, and about 3 mgto about 200 mg. The amount of antiarrhythmic pharmaceutical agent forthe treatment of arrhythmia can be at least about 0.1 mg, such as atleast about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5,3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60,70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450,or 500 mg. The amount of antiarrhythmic pharmaceutical agent for thetreatment of arrhythmia can range about 0.01-500 mg, such as about0.1-500, 0.1-450, 0.1-400, 0.1-350, 0.1-300, 0.1-250, 0.1-200, 0.1-150,0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10, 0.1-5,0.1-1.0, 0.1-0.5, 1-500, 1-450, 1-400, 1-350, 1-300, 1-250, 1-200,1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5, 5-500, 5-450,5-400, 5-350, 5-300, 5-250, 5-200, 5-150, 5-130, 5-110, 5-90, 5-70,5-50, 5-30, 5-10, 10-500, 10-450, 10-400, 10-350, 10-300, 10-250,10-200, 10-150, 10-130, 10-110, 10-90, 10-70, 10-50, 10-30, 30-500,30-450, 30-400, 30-350, 30-300, 30-250, 30-200, 30-150, 30-130, 30-110,30-90, 30-70, 30-50, 50-500, 50-450, 50-400, 50-350, 50-300, 50-250,50-200, 50-150, 50-130, 50-110, 50-90, 50-70, 70-500, 70-450, 70-400,70-350, 70-300, 70-250, 70-200, 70-150, 70-130, 70-110, 70-90, 90-500,90-450, 90-400, 90-350, 90-300, 90-250, 90-200, 90-150, 90-130, 90-110,110-500, 110-450, 110-400, 110-350, 110-300, 110-250, 110-200, 110-150,110-130, 130-500, 130-450, 130-400, 130-350, 130-300, 130-250, 130-200,130-150, 150-500, 150-450, 150-400, 150-350, 150-300, 150-250, 150-200,200-500, 200-450, 200-400, 200-350, 200-300, 200-250, 250-500, 250-450,250-400, 250-350, 250-300, 300-500, 300-450, 300-400, 300-350, 350-500,350-450, 350-400, 400-500, 400-450, or 450-500 mg. For example, theamount of antiarrhythmic pharmaceutical agent for the treatment ofarrhythmia can range about from 0.1 to about 5 mg.

The dose may be administered during a single inhalation or may beadministered during several inhalations. The fluctuations ofantiarrhythmic pharmaceutical agent concentration can be reduced byadministering the pharmaceutical composition more often or may beincreased by administering the pharmaceutical composition less often.Therefore, the pharmaceutical composition of one or more embodiments ofthe present invention may be administered from about four times daily toabout once a month, such as about once daily to about once every twoweeks, about once every two days to about once a week, and about onceper week. The pharmaceutical composition can also be administered to thepatient on an as-needed basis.

For treating a patient suffering from an arrhythmia, the amount per doseof antiarrhythmic pharmaceutical agent administered may be an amountthat is effective to treat the arrhythmia. The amount of antiarrhythmicpharmaceutical agent for the treatment of arrhythmia will generally behigher than that used for prevention, and will typically range fromabout 0.001 mg/kg to 6 mg/kg, such as from about 0.002 mg/kg to about 5mg/kg, or from about 0.005 mg/kg to about 4 mg/kg. In one exemplarytreatment regimen, the formulation in accordance with one or moreembodiments of the invention may be administered about 1 to about 4times daily, such as from about 2 to about 3 times daily. Generally, thedose of antiarrhythmic pharmaceutical agent delivered to a patient willrange from about 0.1 mg to about 600 mg, such as from about 0.2 mg to500 mg daily, depending on the condition being treated, the age andweight of the patient, and the like.

In some cases, the amount of antiarrhythmic pharmaceutical agent for thetreatment of arrhythmia can be at least about 0.001 mg/kg, such as atleast about 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg, 0.1mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg,0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg,3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg. The amount of antiarrhythmicpharmaceutical agent for the treatment of arrhythmia can range fromabout 0.001 mg/kg to 20 mg/kg, such as from about 0.001 mg/kg to about0.01 mg/kg, from about 0.01 mg/kg to about 0.05 mg/kg, from about 0.05mg/kg to about 0.1 mg/kg, from about 0.1 mg/kg to about 0.2 mg/kg, fromabout 0.5 mg/kg to from about 0.1 mg/kg to about 1 mg/kg, from about 0.1mg/kg to about 2 mg/kg, from about 0.1 mg/kg to about 3 mg/kg, fromabout 0.3 mg/kg to about 1 mg/kg, from about 0.3 mg/kg to about 2 mg/kg,from about 0.3 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 1mg/kg, from about 0.5 mg/kg to about 2 mg/kg, from about 0.5 mg/kg toabout 3 mg/kg, from about 0.5 mg/kg to about 6 mg/kg, from about 0.7mg/kg to about 1 mg/kg, from about 0.7 mg/kg to about 2 mg/kg, fromabout 0.7 mg/kg to about 4 mg/kg, from about 0.7 mg/kg to about 6 mg/kg,from about 1 mg/kg to about 2 mg/kg, from about 1 mg/kg to about 4mg/kg, from about 1 mg/kg to about 6 mg/kg, from about 1 mg/kg to about8 mg/kg, from about 1 mg/kg to about 10 mg/kg, from about 1 mg/kg toabout 15 mg/kg, from about 1 mg/kg to about 20 mg/kg, from about 2 mg/kgto about 3 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 2mg/kg to about 6 mg/kg, from about 2 mg/kg to about 8 mg/kg, from about2 mg/kg to about 10 mg/kg, from about 2 mg/kg to about 15 mg/kg, fromabout 2 mg/kg to about 20 mg/kg, from about 3 mg/kg to about 4 mg/kg,from about 3 mg/kg to about 5 mg/kg, from about 3 mg/kg to about 6mg/kg, from about 3 mg/kg to about 8 mg/kg, from about 3 mg/kg to about10 mg/kg, from about 3 mg/kg to about 15 mg/kg, from about 3 mg/kg toabout 20 mg/kg, from about 4 mg/kg to about 5 mg/kg, from about 4 mg/kgto about 6 mg/kg, from about 4 mg/kg to about 8 mg/kg, from about 4mg/kg to about 10 mg/kg, from about 4 mg/kg to about 15 mg/kg, fromabout 4 mg/kg to about 20 mg/kg, from about 6 mg/kg to about 8 mg/kg,from about 6 mg/kg to about 10 mg/kg, from about 6 mg/kg to about 15mg/kg, from about 6 mg/kg to about 20 mg/kg, from about 8 mg/kg to about10 mg/kg, from about 8 mg/kg to about 15 mg/kg, from about 8 mg/kg toabout 20 mg/kg, from about 10 mg/kg to about 15 mg/kg, from about 10mg/kg to about 20 mg/kg, or from about 15 mg/kg to about 20 mg/kg.

For instance, the present invention may involve a follow-up inhalationif no cardioversion occurs after an initial inhalation. Typically, if nocardioversion occurs within 30 minutes of the initial inhalation, thefollow-up dosage is higher or the same as the initial dosage.

The dosing may be guided by how the patient feels. Also oralternatively, dosing may be guided by using a portable/mobile ECGdevice. For instance, the dosing may be guided by using a Holtermonitor.

In another version, the pharmaceutical composition is administeredprophylactically to a patient who is likely to develop an arrhythmia.For example, a patient who has a history of arrhythmias can beprophylactically treated with a pharmaceutical composition comprisingantiarrhythmic pharmaceutical agent to reduce the likelihood ofdeveloping an arrhythmia.

The pharmaceutical composition may be administered to a patient in anyregimen which is effective to prevent an arrhythmia. Illustrativeprophylactic regimes include administering an antiarrhythmicpharmaceutical agent as described herein 1 to 21 times per week.

While not wishing to be bound by theory, by providing the antiarrhythmicpharmaceutical agent in accordance with one or more embodiments of theinvention, the systemic exposure of the antiarrhythmic pharmaceuticalagent can be reduced by avoiding initial dilution. As noted above, theantiarrhythmic pharmaceutical agent undergoes dilution as and after itpasses through the heart. Thus, the administration via inhalation ofantiarrhythmic pharmaceutical agent is believed to be safer thanintravenous delivery.

In another aspect, a method of administering comprises administering tofree breathing patients by way of an aerosol generator device and/orsystem for administration of aerosolized medicaments such as thosedisclosed in U.S. Published Application Nos. 20050235987, 20050211253,20050211245, 20040035413, and 20040011358, the disclosures of which areincorporated herein by reference in their entireties.

In one version, the pharmaceutical composition may be delivered to thelungs of a patient in the form of a dry powder. Accordingly, thepharmaceutical composition comprises a dry powder that may beeffectively delivered to the deep lungs or to another target site. Thispharmaceutical composition is in the form of a dry powder comprisingparticles having a size selected to permit penetration into the alveoliof the lungs. In one version, the pharmaceutical composition may bedelivered by extruding a liquid through micron or submicron-sized holeswith subsequent Rayleigh break-up into fine droplets.

In some instances, it is desirable to deliver a unit dose, such as dosesof 0.1 mg or 100 mg or greater of an antiarrhythmic pharmaceutical agentto the lung in a single inhalation. The above described phospholipidhollow and/or porous dry powder particles allow for doses of about 5 mgor greater, often greater than about 10 mg, sometimes greater than about15 mg, sometimes greater than about 20 mg, sometimes greater than about25 mg, and sometimes greater than about 30 mg, to be delivered in asingle inhalation and in an advantageous manner. Alternatively, a dosagemay be delivered over two or more inhalations, such as 1 to 6, 1 to 5,or 1 to 4, inhalations. For example, a 10 mg dosage may be delivered byproviding two unit doses of 5 mg each, and the two unit doses may beseparately inhaled. In certain embodiments, the overall dose of theantiarrhythmic pharmaceutical agent ranges from 0.1 mg to 200 mg, suchas 0.5 mg to 150 mg, or 1 mg to 100 mg.

In some cases, a dosage may be delivered over two or more inhalations,such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95or 100 inhalations. A dosage may also be delivered over 1 to 100inhalations, such as 1-3, 1-4, 1-5, 1-6, 1-10, 1-20, 1-50, 1-80, 1-100,2-5, 2-6, 2-10, 2-20, 2-50, 2-100, 5-10, 5-20, 5-50, 5-100, 10-20,10-50, 10-100, 20-50, 20-100, or 50-100 inhalations. For example, a 10mg dosage may be delivered by providing two unit doses of 5 mg each, andthe two unit doses may be separately inhaled. In certain embodiments,the overall dose of the antiarrhythmic pharmaceutical agent ranges fromabout 0.01-500 mg, such as about 0.1-500, 0.1-450, 0.1-400, 0.1-350,0.1-300, 0.1-250, 0.1-200, 0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70,0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0, 0.1-0.5, 1-500, 1-450, 1-400,1-350, 1-300, 1-250, 1-200, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30,1-10, 1-5, 5-500, 5-450, 5-400, 5-350, 5-300, 5-250, 5-200, 5-150,5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-500, 10-450, 10-400,10-350, 10-300, 10-250, 10-200, 10-150, 10-130, 10-110, 10-90, 10-70,10-50, 10-30, 30-500, 30-450, 30-400, 30-350, 30-300, 30-250, 30-200,30-150, 30-130, 30-110, 30-90, 30-70, 30-50, 50-500, 50-450, 50-400,50-350, 50-300, 50-250, 50-200, 50-150, 50-130, 50-110, 50-90, 50-70,70-500, 70-450, 70-400, 70-350, 70-300, 70-250, 70-200, 70-150, 70-130,70-110, 70-90, 90-500, 90-450, 90-400, 90-350, 90-300, 90-250, 90-200,90-150, 90-130, 90-110, 110-500, 110-450, 110-400, 110-350, 110-300,110-250, 110-200, 110-150, 110-130, 130-500, 130-450, 130-400, 130-350,130-300, 130-250, 130-200, 130-150, 150-500, 150-450, 150-400, 150-350,150-300, 150-250, 150-200, 200-500, 200-450, 200-400, 200-350, 200-300,200-250, 250-500, 250-450, 250-400, 250-350, 250-300, 300-500, 300-450,300-400, 300-350, 350-500, 350-450, 350-400, 400-500, 400-450, or450-500 mg. For example, the amount of antiarrhythmic pharmaceuticalagent for the treatment of arrhythmia can range about from 0.1 to about5 mg. In some instances the antiarrhythmic agent can be administeredas-needed titrating the dosage to effect.

The time for dosing is typically short. For nebulizers the dosing timeusually ranges from 1 minute to 20 minutes, such as from 2 minutes to 15minutes, or from 3 minutes to 10 minutes. Regarding dry powders, for asingle capsule, the total dosing time is normally less than about 1minute. Thus, the time for dosing may be less than about 5 min, such asless than about 4 min, less than about 3 min, less than about 2 min, orless than about 1 min.

In certain embodiments, the present invention is directed to a method ofdiagnosis by a health care provider followed by treatment of atrialarrhythmia. In certain embodiments, the present invention is directed toa method of self-diagnosing and treating atrial arrhythmia. The methodcomprises diagnosing or self-diagnosing atrial arrhythmia by detectingat least one of shortness of breath, heart palpitations, and abovenormal heart rate. The method also comprises self-administering byinhalation an effective amount of at least one antiarrhythmicpharmaceutical agent within two hours, such as within one hour, 30minutes, or within 15 minutes, of the self-diagnosing.

In certain embodiments, the patient can self-titrate. For example, thepatient can self-administer, e.g., by using a nebulizer, until disablingsymptoms disappear. In some cases, the self-administering continuesuntil the patient no longer feels heart palpitations, or until thepatient detects the restoration of normal sinus rhythm using aportable/mobile ECG device (which can be worn by the patient, such as awatch; or otherwise carried by the patient, such as an over the skinpatch or an implantable device connected to a smart phone or watch).

The time for onset of action is also typically short. For instance, thepatient may have normal sinus rhythm within 20 minutes of initiating theadministering, such as within 15 minutes, within 10 minutes, or within 5minutes of initiating the administering. The rapid onset of action isadvantageous because the longer a patient has had arrhythmia, the longerit typically takes to convert the patient to normal sinus rhythm.

In some embodiments, the method of the present invention allows thepatient to avoid other therapies, such as ablation and/or electricalcardioversion. In other embodiments, the method of the present inventionis used in combination with other therapies, such as before or afterelectrical cardioversion and/or ablation therapy.

The dispersions or powder pharmaceutical compositions may beadministered using an aerosolization device. The aerosolization devicemay be a nebulizer, a metered dose inhaler, a liquid dose instillationdevice, or a dry powder inhaler. The aerosolization device may comprisethe extrusion of the pharmaceutical preparation through micron orsubmicron-sized holes with subsequent Rayleigh break-up into finedroplets. The pharmaceutical composition may be delivered by a nebulizeras described in WO 99/16420, by a metered dose inhaler as described inWO 99/16422, by a liquid dose instillation apparatus as described in WO99/16421, and by a dry powder inhaler as described in U.S. PublishedApplication Nos. 20020017295 and 20040105820, WO 99/16419, WO 02/83220,and U.S. Pat. No. 6,546,929, which are incorporated herein by referencein their entireties. As such, an inhaler may comprise a canistercontaining the particles or particles and propellant, and wherein theinhaler comprises a metering valve in communication with an interior ofthe canister. The propellant may be a hydrofluoroalkane.

The formulations of the present invention may be administered withnebulizers, such as that disclosed in PCT WO 99/16420, the disclosure ofwhich is hereby incorporated in its entirety by reference, in order toprovide an aerosolized medicament that may be administered to thepulmonary air passages of a patient in need thereof. Nebulizers areknown in the art and could easily be employed for administration of theclaimed formulations without undue experimentation. Breath activated orbreath-actuated nebulizers, as well as those comprising other types ofimprovements which have been, or will be, developed are also compatiblewith the formulations of the present invention and are contemplated asbeing within the scope thereof.

In some cases, the nebulizer is a breath activated or breath-actuatednebulizer. In some cases, the nebulizer is a hand-held inhaler device(e.g., AeroEclipse® II Breath Actuated Nebulizer (BAN)). In some cases,the nebulizer has a compressed air source. In some cases, the nebulizerconverts liquid medication into an aerosol. In some cases, the nebulizerconverts liquid medication into an aerosol by extruding thepharmaceutical preparation through micron or submicron-sized holes. Insome cases, the nebulizer converts liquid medication into an aerosol soit can be inhaled into the lungs. In some cases, the nebulizer is asmall volume nebulizer. In some cases, the nebulizer is a small volumejet nebulizer. In some cases, aerosolized medication is only producedwhen inhaled through the device. In some cases, the medication iscontained in the cup between breaths or during breaks in treatment. Insome cases, the medication is contained in the cup until ready to beinhaled.

Nebulizers impart energy into a liquid pharmaceutical formulation toaerosolize the liquid, and to allow delivery to the pulmonary system,e.g., the lungs, of a patient. A nebulizer comprises a liquid deliverysystem, such as a container having a reservoir that contains a liquidpharmaceutical formulation. The liquid pharmaceutical formulationgenerally comprises an active agent that is either in solution orsuspended within a liquid medium.

In one type of nebulizer, generally referred to as a jet nebulizer,compressed gas is forced through an orifice in the container. Thecompressed gas forces liquid to be withdrawn through a nozzle, and thewithdrawn liquid mixes with the flowing gas to form aerosol droplets. Acloud of droplets is then administered to the patients respiratorytract.

In another type of nebulizer, generally referred to as a vibrating meshnebulizer, energy, such as mechanical energy, vibrates a mesh. Thisvibration of the mesh aerosolizes the liquid pharmaceutical formulationto create an aerosol cloud that is administered to the patient's lungs.In another type of nebulizer the nebulizing comprises extrusion throughmicron or submicron-sized holes followed by Rayleigh break-up into finedroplets.

Alternatively or additionally, the pharmaceutical formulation may be ina liquid form and may be aerosolized using a nebulizer as described inWO 2004/071368, which is herein incorporated by reference in itsentirety, as well as U.S. Published application Nos. 2004/0011358 and2004/0035413, which are both herein incorporated by reference in theirentireties. Other examples of nebulizers include, but are not limitedto, the Aeroneb®Go or Aeroneb®Pro nebulizers, available from AerogenLtd. of Galway, Ireland; the PARI eFlow and other PART nebulizersavailable from PARI Respiratory Equipment, Inc. of Midlothian, Va.; theLumiscope® Nebulizer 6600 or 6610 available from Lumiscope Company, Inc.of East Brunswick, N.J.; and the Omron NE-U22 available from OmronHealthcare, Inc. of Kyoto, Japan. Other examples of nebulizers includedevices produced by Medspray (Enschede, The Netherlands).

It has been found that a nebulizer of the vibrating mesh type, such asone that that forms droplets without the use of compressed gas, such asthe Aeroneb® Pro provides unexpected improvement in dosing efficiencyand consistency. By generating fine droplets by using a vibratingperforated or unperforated membrane, rather than by introducingcompressed air, the aerosolized pharmaceutical formulation can beintroduced without substantially affecting the flow characteristics. Inaddition, the generated droplets when using a nebulizer of this type areintroduced at a low velocity, thereby decreasing the likelihood of thedroplets being driven to an undesired region. It has been found thatwhen using a nebulizer of the extrusion/Rayleigh jet breakup type, thegenerated droplets are also introduced at a low velocity, therebydecreasing the likelihood of the droplets being driven to an undesiredregion.

In some cases, the nebulizer can be of the vibrating mesh type. In somecases, the nebulizer can be of the pressurized jet type. In some cases,the nebulizer can be of the extrusion/Rayleigh breakup type. In somecases, the nebulizer is lightweight (at most 60 g, at most 100 g, atmost 200 g, at most 250 g) and nearly silent. In some cases, thenebulizer has a sound level less than 35 A-weighted decibels (dBA) at 1meter. In some cases, the nebulizer has a medication cup capacity of 6mL. In some cases, the nebulizer has a residual volume of less than 0.3mL. In some cases, the nebulizer generates an average flow rate of 0.4mL/min. In some cases, the nebulizer generates an average flow rate of0.5 mL/min. In some cases, the nebulizer generates an average flow rateof 0.6 mL/min. In some cases, the nebulizer generates an average flowrate of 0.7 mL/min. In some cases, the nebulizer generates an averageflow rate of 0.8 mL/min. In some cases, the nebulizer generates anaverage flow rate of 0.9 mL/min. In some cases, the nebulizer generatesan average flow rate of 1.0 mL/min. In some cases, the nebulizergenerates an average flow rate of 1.1 mL/min. In some cases, thenebulizer generates an average flow rate of 1.2 mL/min. In some cases,the nebulizer generates an average particle size of 3.0 μm MMAD. In somecases, the nebulizer generates an average particle size between 3.0 μmMMAD and 4.0 μm MMAD. In some cases, the nebulizer generates an averageparticle size of 3.0 μm MMAD. In some cases, the nebulizer generates anaverage particle size between 3.0 μm MMAD and 5.0 μm MMAD. In somecases, the nebulizer generates an average particle size of 3.0 μm MMAD.In some cases, the nebulizer generates an average particle size between3.0 μm MMAD and 6.0 μm MMAD.

In still another type of nebulizer, ultrasonic waves are generated todirectly vibrate and aerosolize the pharmaceutical formulation.

As noted above, the present invention may also involve a dry powderinhaler. A specific version of a dry powder aerosolization apparatus isdescribed in U.S. Pat. Nos. 4,069,819 and 4,995,385, which areincorporated herein by reference in their entireties. Another usefuldevice, which has a chamber that is sized and shaped to receive acapsule so that the capsule is orthogonal to the inhalation direction,is described in U.S. Pat. No. 3,991,761, which is incorporated herein byreference in its entirety. As also described in U.S. Pat. No. 3,991,761,a puncturing mechanism may puncture both ends of the capsule. In anotherversion, a chamber may receive a capsule in a manner where air flowsthrough the capsule as described for example in U.S. Pat. Nos. 4,338,931and 5,619,985, which are incorporated herein by reference in theirentireties. In another version, the aerosolization of the pharmaceuticalcomposition may be accomplished by pressurized gas flowing through theinlets, as described for example in U.S. Pat. Nos. 5,458,135; 5,785,049;and 6,257,233, or propellant, as described in WO 00/72904 and U.S. Pat.No. 4,114,615, which are incorporated herein by reference. These typesof dry powder inhalers are generally referred to as active dry powderinhalers.

Other dry powder inhalers include those available from BoehringerIngelheim (e.g., Respimat inhaler), Hovione (e.g., FlowCaps inhaler),Plastiape (e.g., Osmohaler inhaler), and MicroDose. The presentinvention may also utilize condensation aerosol devices, available fromAlexza, Mountain View, Calif. Yet another useful inhaler is disclosed inWO 2008/051621, which is incorporated herein by reference in itsentirety.

The pharmaceutical formulations disclosed herein may also beadministered to the lungs of a patient via aerosolization, such as witha metered dose inhaler. The use of such formulations provides forsuperior dose reproducibility and improved lung deposition as disclosedin WO 99/16422, hereby incorporated in its entirety by reference. MDIsare known in the art and could easily be employed for administration ofthe claimed dispersions without undue experimentation. Breath-activatedor breath-actuated MDIs and pressurized MDIs (pMDIs), as well as thosecomprising other types of improvements which have been, or will be,developed are also compatible with the formulations of the presentinvention and, as such, are contemplated as being within the scopethereof.

Along with DPIs, MDIs and nebulizers, it will be appreciated that theformulations of one or more embodiments of the present invention may beused in conjunction with liquid dose instillation or LDI techniques asdisclosed in, for example, WO 99/16421, which is incorporated herein byreference in its entirety. Liquid dose instillation involves the directadministration of a formulation to the lung. With respect to LDI theformulations are preferably used in conjunction with partial liquidventilation or total liquid ventilation. Moreover, one or moreembodiments of the present invention may further comprise introducing atherapeutically beneficial amount of a physiologically acceptable gas(such as nitric oxide or oxygen) into the pharmaceutical microdispersionprior to, during or following administration.

The pharmaceutical composition of one or more embodiments of the presentinvention typically has improved emitted dose efficiency. Accordingly,high doses of the pharmaceutical composition may be delivered using avariety of aerosolization devices and techniques.

The emitted dose (ED) of the particles of the present invention may begreater than about 30%, such as greater than about 40%, greater thanabout 50%, greater than about 60%, or greater than about 70%.

One or more embodiments are directed to kits. For instance, the kit mayinclude an aerosolization device and a container, e.g., unit dosereceptacle, containing aerosolizable antiarrhythmic pharmaceuticalagent, e.g., liquid or dry powder.

The kit may further comprise a package, such as a bag, that contains theaerosolization device and the container.

In view of the above, the present invention involves methods to treatacute episodes of and/or chronic arrhythmias. In certain embodiments,the treating comprises acute treatment after detection of atrialarrhythmia.

This method of treatment results in a pulsatile pharmacokinetic profileand transient pharmacodynamic effect mimicking the effect of an IV. Thismethod delivers high drug concentrations that are safe and effective tothe heart, while the distribution to the rest of the body results in thedrug being diluted to sub-therapeutic levels. This method is theshortest route of delivery to the heart next to intra-cardial injection.This provides the convenience of self-administration like the“pill-in-the-pocket” approach, but the effectiveness and fast onset ofaction of an IV. Although the delivery of medications through the lungfor systemic effect is not new, it was thought it wouldn't be effectiveto the heart, because of the fast passage of drug through it. The animaland human PK/PD data in this study show that the drug exposure issufficient for therapeutic effect at a much lower dose compared to otherroutes of administration. This method ensures dug concentrations inoverall plasma are much lower than what is achieved by oral/IV henceminimizing drug-drug interactions and side effects.

In some cases, the T_(max) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 0.1 minute to about 30minutes, such as 0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-3,0.1-3.5, 0.1-4, 0.1-4.5, 0.1-5, 0.1-6, 0.1-8, 0.1-10, 0.1-15, 0.1-20,0.1-25, 0.1-30, 0.2-0.5, 0.2-1, 0.2-1.5, 0.2-2, 0.2-2.5, 0.2-3, 0.2-3.5,0.2-4, 0.2-4.5, 0.2-5, 0.2-6, 0.2-8, 0.2-10, 0.2-15, 0.2-20, 0.2-25,0.2-30, 0.3-0.5, 0.3-1, 0.3-1.5, 0.3-2, 0.3-2.5, 0.3-3, 0.3-3.5, 0.3-4,0.3-4.5, 0.3-5, 0.3-6, 0.3-8, 0.3-10, 0.3-15, 0.3-20, 0.3-25, 0.3-30,0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4, 0.5-4.5, 0.5-5,0.5-6, 0.5-8, 0.5-10, 0.5-15, 0.5-20, 0.5-25, 0.5-30, 1-1.5, 1-2, 1-2.5,1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1-6, 1-8, 1-10, 1-15, 1-20, 1-25, 1-30,1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 1.5-6, 1.5-8,1.5-10, 1.5-15, 1.5-20, 1.5-25, 1.5-30, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5,2-5, 2-6, 2-8, 2-10, 2-15, 2-20, 2-25, 2-30, 2.5-3, 2.5-3.5, 2.5-4,2.5-4.5, 2.5-5, 2.5-6, 2.5-8, 2.5-10, 2.5-15, 2.5-20, 2.5-25, 2.5-30,3-3.5, 3-4, 3-4.5, 3-5, 3-6, 3-8, 3-10, 3-15, 3-20, 3-25, 3-30, 3.5-4,3.5-4.5, 3.5-5, 3.5-6, 3.5-8, 3.5-10, 3.5-15, 3.5-20, 3.5-25, 3.5-30,4-4.5, 4-5, 4-6, 4-8, 4-10, 4-15, 4-20, 4-25, 4-30, 4.5-5, 4.5-6, 4.5-8,4.5-10, 4.5-15, 4.5-20, 4.5-25, 4.5-30, 5-6, 5-8, 5-10, 5-15, 5-20,5-25, 5-30, 5.5-6, 5.5-8, 5.5-10, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 6-8,6-10, 6-15, 6-20, 6-25, 6-30, 8-10, 8-15, 8-20, 8-25, 8-30, 10-15,10-20, 10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30, or 25-30 min. Arange given out in the present disclosure can be a range between twoaccurate numerical values, in some cases, a range in the presentdisclosure can also refer to a range between two approximate numericalvalues. For instance, “1-10” can refer to “from 1 to 10” in some cases,while in other case, “1-10” can refer to “from about 1 to about 10”. Insome cases, the T_(max) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be 0.01-5, 0.02-5, 0.03-5, 0.04-5,0.05-5, 0.06-5, 0.07-5, 0.08-5, 0.09-5, 0.12-5, 0.14-5, 0.15-5, 0.16-5,0.18-5, 0.2-5, 0.24-5, 0.26-5, 0.28-5, 0.3-5, 0.35-5, 0.4-5, 0.5-5,0.6-5, 0.7-5, 0.8-5, 0.9-5, or 1-5 min. In some cases, the T_(max) ofthe antiarrhythmic pharmaceutical agent administered via inhalation canbe from about 0.1 to about 3 min. In some cases, the T_(max) of theantiarrhythmic pharmaceutical agent administered via inhalation can befrom about 0.1 to about 5 min. In some cases, the T_(max) of theantiarrhythmic pharmaceutical agent (e.g., flecainide) administered viainhalation can be from about 0.2 to about 5 min. In one or moreembodiments, the antiarrhythmic pharmaceutical agent is a class I, classII, class III, or class IV antiarrhythmic. In some embodiments, theantiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic. Inother embodiments, the antiarrhythmic pharmaceutical agent is flecainideor a pharmaceutically acceptable salt thereof.

In some cases, the T_(max) can be calculated as the amount of time atwhich the maximum plasma concentration of the antiarrhythmicpharmaceutical agent is observed. In some cases, the T_(max) can becalculated as the amount of time after administration of theantiarrhythmic pharmaceutical agent when the maximum plasmaconcentration is reached. In some cases, the T_(max) can be calculatedas the amount of time after the initiation of the administration of theantiarrhythmic pharmaceutical agent when the maximum plasmaconcentration is reached. In some cases, the T_(max) can be calculatedas the amount of time after the completion of the administration of theantiarrhythmic pharmaceutical agent when the maximum plasmaconcentration is reached. In some cases, the T_(max) can be calculatedfrom plasma concentration of the antiarrhythmic pharmaceutical agentmeasured in the left ventricular chamber. In some cases, the T_(max) canbe calculated from plasma concentration of the antiarrhythmicpharmaceutical agent measured in the pulmonary artery. In some cases,the T_(max) can be calculated from plasma concentration of theantiarrhythmic pharmaceutical agent measured in the vein (e.g., femoralvein). In some cases, the T_(max) can be measured in a human PK/PDstudy. The term “human PK/PD study” as used herein can refer to anysettings where a human subject receives administration of a single doseof the antiarrhythmic agent as provided herein and a pharmacokinetic(PK) or pharmacodynamic (PD) parameter is measured from the humansubject after the administration of the antiarrhythmic agent. In somecases, a human PK/PD study as provided herein can refer to a clinicalstudy performed in a clinic or hospital settings. In some cases, thehuman PK/PD study can be a single center or multi-center study. A humanPK/PD study can be performed on healthy human subjects or humancardiovascular patients. In some cases, the patients with cardiovasculardisease experience arrhythmia as described herein. In some cases, ahuman PK/PD study can be a single-dose study, in other cases, a humanPK/PD study can be a multi-dose (e.g. escalating doses) study.

In some cases, the C_(max) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 10 ng/mL to about 5000ng/mL, such as from about 10-30, 10-50, 10-70, 10-80, 10-90, 10-100,10-110, 10-120, 10-130, 10-140, 10-150, 10-160, 10-170, 10-180, 10-190,10-200, 10-250, 10-300, 10-350, 10-400, 10-450, 10-500, 10-550, 10-600,10-650, 10-700, 10-800, 10-900, 10-1000, 10-1500, 10-2000, 10-3000,10-4000, 10-5000, 20-30, 20-50, 20-70, 20-80, 20-90, 20-100, 20-110,20-120, 20-130, 20-140, 20-150, 20-160, 20-170, 20-180, 20-190, 20-200,20-250, 20-300, 20-350, 20-400, 20-450, 20-500, 20-550, 20-600, 20-650,20-700, 20-800, 20-900, 20-1000, 20-1500, 20-2000, 20-3000, 20-4000,20-5000, 30-50, 30-70, 30-80, 30-90, 30-100, 30-110, 30-120, 30-130,30-140, 30-150, 30-160, 30-170, 30-180, 30-190, 30-200, 30-250, 30-300,30-350, 30-400, 30-450, 30-500, 30-550, 30-600, 30-650, 30-700, 30-800,30-900, 30-1000, 30-1500, 30-2000, 30-3000, 30-4000, 30-5000, 50-70,50-80, 50-90, 50-100, 50-110, 50-120, 50-130, 50-140, 50-150, 50-160,50-170, 50-180, 50-190, 50-200, 50-250, 50-300, 50-350, 50-400, 50-450,50-500, 50-550, 50-600, 50-650, 50-700, 50-800, 50-900, 50-1000,50-1500, 50-2000, 50-3000, 50-4000, 50-5000, 70-80, 70-90, 70-100,70-110, 70-120, 70-130, 70-140, 70-150, 70-160, 70-170, 70-180, 70-190,70-200, 70-250, 70-300, 70-350, 70-400, 70-450, 70-500, 70-550, 70-600,70-650, 70-700, 70-800, 70-900, 70-1000, 70-1500, 70-2000, 70-3000,70-4000, 70-5000, 80-90, 80-100, 80-110, 80-120, 80-130, 80-140, 80-150,80-160, 80-170, 80-180, 80-190, 80-200, 80-250, 80-300, 80-350, 80-400,80-450, 80-500, 80-550, 80-600, 80-650, 80-700, 80-800, 80-900, 80-1000,80-1500, 80-2000, 80-3000, 80-4000, 80-5000, 90-100, 90-110, 90-120,90-130, 90-140, 90-150, 90-160, 90-170, 90-180, 90-190, 90-200, 90-250,90-300, 90-350, 90-400, 90-450, 90-500, 90-550, 90-600, 90-650, 90-700,90-800, 90-900, 90-1000, 90-1500, 90-2000, 90-3000, 90-4000, 90-5000,100-110, 100-120, 100-130, 100-140, 100-150, 100-160, 100-170, 100-180,100-190, 100-200, 100-250, 100-300, 100-350, 100-400, 100-450, 100-500,100-550, 100-600, 100-650, 100-700, 100-800, 100-900, 100-1000,100-1500, 100-2000, 100-3000, 100-4000, 100-5000, 110-120, 110-130,110-140, 110-150, 110-160, 110-170, 110-180, 110-190, 110-200, 110-250,110-300, 110-350, 110-400, 110-450, 110-500, 110-550, 110-600, 110-650,110-700, 110-800, 110-900, 110-1000, 110-1500, 110-2000, 110-3000,110-4000, 110-5000, 120-130, 120-140, 120-150, 120-160, 120-170,120-180, 120-190, 120-200, 120-250, 120-300, 120-350, 120-400, 120-450,120-500, 120-550, 120-600, 120-650, 120-700, 120-800, 120-900, 120-1000,120-1500, 120-2000, 120-3000, 120-4000, 120-5000, 130-140, 130-150,130-160, 130-170, 130-180, 130-190, 130-200, 130-250, 130-300, 130-350,130-400, 130-450, 130-500, 130-550, 130-600, 130-650, 130-700, 130-800,130-900, 130-1000, 130-1500, 130-2000, 130-3000, 130-4000, 130-5000,140-150, 140-160, 140-170, 140-180, 140-190, 140-200, 140-250, 140-300,140-350, 140-400, 140-450, 140-500, 140-550, 140-600, 140-650, 140-700,140-800, 140-900, 140-1000, 140-1500, 140-2000, 140-3000, 140-4000,140-5000, 150-160, 150-170, 150-180, 150-190, 150-200, 150-250, 150-300,150-350, 150-400, 150-450, 150-500, 150-550, 150-600, 150-650, 150-700,150-800, 150-900, 150-1000, 150-1500, 150-2000, 150-3000, 150-4000,150-5000, 160-170, 160-180, 160-190, 160-200, 160-250, 160-300, 160-350,160-400, 160-450, 160-500, 160-550, 160-600, 160-650, 160-700, 160-800,160-900, 160-1000, 160-1500, 160-2000, 160-3000, 160-4000, 160-5000,170-180, 170-190, 170-200, 170-250, 170-300, 170-350, 170-400, 170-450,170-500, 170-550, 170-600, 170-650, 170-700, 170-800, 170-900, 170-1000,170-1500, 170-2000, 170-3000, 170-4000, 170-5000, 180-190, 180-200,180-250, 180-300, 180-350, 180-400, 180-450, 180-500, 180-550, 180-600,180-650, 180-700, 180-800, 180-900, 180-1000, 180-1500, 180-2000,180-3000, 180-4000, 180-5000, 190-200, 190-250, 190-300, 190-350,190-400, 190-450, 190-500, 190-550, 190-600, 190-650, 190-700, 190-800,190-900, 190-1000, 190-1500, 190-2000, 190-3000, 190-4000, 190-5000,200-250, 200-300, 200-350, 200-400, 200-450, 200-500, 200-550, 200-600,200-650, 200-700, 200-800, 200-900, 200-1000, 200-1500, 200-2000,200-3000, 200-4000, 200-5000, 250-300, 250-350, 250-400, 250-450,250-500, 250-550, 250-600, 250-650, 250-700, 250-800, 250-900, 250-1000,250-1500, 250-2000, 250-3000, 250-4000, 250-5000, 300-350, 300-400,300-450, 300-500, 300-550, 300-600, 300-650, 300-700, 300-800, 300-900,300-1000, 300-1500, 300-2000, 300-3000, 300-4000, 300-5000, 350-400,350-450, 350-500, 350-550, 350-600, 350-650, 350-700, 350-800, 350-900,350-1000, 350-1500, 350-2000, 350-3000, 350-4000, 350-5000, 400-450,400-500, 400-550, 400-600, 400-650, 400-700, 400-800, 400-900, 400-1000,400-1500, 400-2000, 400-3000, 400-4000, 400-5000, 450-500, 450-550,450-600, 450-650, 450-700, 450-800, 450-900, 450-1000, 450-1500,450-2000, 450-3000, 450-4000, 450-5000, 500-550, 500-600, 500-650,500-700, 500-800, 500-900, 500-1000, 500-1500, 500-2000, 500-3000,500-4000, 500-5000, 550-600, 550-650, 550-700, 550-800, 550-900,550-1000, 550-1500, 550-2000, 550-3000, 550-4000, 550-5000, 600-650,600-700, 600-800, 600-900, 600-1000, 600-1500, 600-2000, 600-3000,600-4000, 600-5000, 650-700, 650-800, 650-900, 650-1000, 650-1500,650-2000, 650-3000, 650-4000, 650-5000, 700-800, 700-900, 700-1000,700-1500, 700-2000, 700-3000, 700-4000, 700-5000, 800-900, 800-1000,800-1500, 800-2000, 800-3000, 800-4000, 800-5000, 900-1000, 900-1500,900-2000, 900-3000, 900-4000, 900-5000, 1000-1500, 1000-2000, 1000-3000,1000-4000, 1000-5000, 1500-2000, 1500-3000, 1500-4000, 1500-5000,2000-3000, 2000-4000, 2000-5000, 3000-4000, 3000-5000, or 4000-5000ng/mL. In some cases, the C_(max) of the antiarrhythmic pharmaceuticalagent administered via inhalation can be from about 20 ng/mL to about500 ng/mL, such as 20-500, 30-500, 40-500, 50-500, 60-500, 70-500,80-500, 90-500, 100-500, 150-500, 200-500, or 250-500 ng/mL. In somecases, the C_(max) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 50 to about 500 ng/mL. Insome cases, the C_(max) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 100 to about 250 ng/mL. Inone or more embodiments antiarrhythmic pharmaceutical agent is a classI, class II, class III, or class IV antiarrhythmic. In some embodiments,the antiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic.In other embodiments, the antiarrhythmic pharmaceutical agent isflecainide or a pharmaceutically acceptable salt thereof.

In some cases, the C_(max) can be calculated as the maximum plasmaconcentration of the antiarrhythmic pharmaceutical agent observed. Insome cases, the C_(max) can be calculated as the peak plasmaconcentration that the antiarrhythmic pharmaceutical agent achievesafter the drug has been administrated. In some cases, the C_(max) can becalculated from plasma concentration of the antiarrhythmicpharmaceutical agent measured in the left ventricular chamber. In somecases, the C_(max) can be calculated from plasma concentration of theantiarrhythmic pharmaceutical agent measured in the pulmonary artery. Insome cases, the C_(max) can be calculated from plasma concentration ofthe antiarrhythmic pharmaceutical agent measured in the vein (e.g.,femoral vein). In some cases, the C_(max) can be measured in a humanPK/PD study.

In some cases, the AUC_(Last) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 100 hr*ng/mL to about10000 hr*ng/mL, such as from 100-200, 100-300, 100-400, 100-420,100-440, 100-460, 100-480, 100-500, 100-520, 100-540, 100-560, 100-580,100-600, 100-620, 100-640, 100-660, 100-680, 100-700, 100-800, 100-900,100-1000, 100-1500, 100-2000, 100-3000, 100-3500, 100-4000, 100-4500,100-5000, 100-5500, 100-6000, 100-6500, 100-7000, 100-8000, 100-9000,100-10000, 200-300, 200-400, 200-420, 200-440, 200-460, 200-480,200-500, 200-520, 200-540, 200-560, 200-580, 200-600, 200-620, 200-640,200-660, 200-680, 200-700, 200-800, 200-900, 200-1000, 200-1500,200-2000, 200-3000, 200-3500, 200-4000, 200-4500, 200-5000, 200-5500,200-6000, 200-6500, 200-7000, 200-8000, 200-9000, 200-10000, 300-400,300-420, 300-440, 300-460, 300-480, 300-500, 300-520, 300-540, 300-560,300-580, 300-600, 300-620, 300-640, 300-660, 300-680, 300-700, 300-800,300-900, 300-1000, 300-1500, 300-2000, 300-3000, 300-3500, 300-4000,300-4500, 300-5000, 300-5500, 300-6000, 300-6500, 300-7000, 300-8000,300-9000, 300-10000, 400-420, 400-440, 400-460, 400-480, 400-500,400-520, 400-540, 400-560, 400-580, 400-600, 400-620, 400-640, 400-660,400-680, 400-700, 400-800, 400-900, 400-1000, 400-1500, 400-2000,400-3000, 400-3500, 400-4000, 400-4500, 400-5000, 400-5500, 400-6000,400-6500, 400-7000, 400-8000, 400-9000, 400-10000, 420-440, 420-460,420-480, 420-500, 420-520, 420-540, 420-560, 420-580, 420-600, 420-620,420-640, 420-660, 420-680, 420-700, 420-800, 420-900, 420-1000,420-1500, 420-2000, 420-3000, 420-3500, 420-4000, 420-4500, 420-5000,420-5500, 420-6000, 420-6500, 420-7000, 420-8000, 420-9000, 420-10000,440-460, 440-480, 440-500, 440-520, 440-540, 440-560, 440-580, 440-600,440-620, 440-640, 440-660, 440-680, 440-700, 440-800, 440-900, 440-1000,440-1500, 440-2000, 440-3000, 440-3500, 440-4000, 440-4500, 440-5000,440-5500, 440-6000, 440-6500, 440-7000, 440-8000, 440-9000, 440-10000,460-480, 460-500, 460-520, 460-540, 460-560, 460-580, 460-600, 460-620,460-640, 460-660, 460-680, 460-700, 460-800, 460-900, 460-1000,460-1500, 460-2000, 460-3000, 460-3500, 460-4000, 460-4500, 460-5000,460-5500, 460-6000, 460-6500, 460-7000, 460-8000, 460-9000, 460-10000,480-500, 480-520, 480-540, 480-560, 480-580, 480-600, 480-620, 480-640,480-660, 480-680, 480-700, 480-800, 480-900, 480-1000, 480-1500,480-2000, 480-3000, 480-3500, 480-4000, 480-4500, 480-5000, 480-5500,480-6000, 480-6500, 480-7000, 480-8000, 480-9000, 480-10000, 500-520,500-540, 500-560, 500-580, 500-600, 500-620, 500-640, 500-660, 500-680,500-700, 500-800, 500-900, 500-1000, 500-1500, 500-2000, 500-3000,500-3500, 500-4000, 500-4500, 500-5000, 500-5500, 500-6000, 500-6500,500-7000, 500-8000, 500-9000, 500-10000, 520-540, 520-560, 520-580,520-600, 520-620, 520-640, 520-660, 520-680, 520-700, 520-800, 520-900,520-1000, 520-1500, 520-2000, 520-3000, 520-3500, 520-4000, 520-4500,520-5000, 520-5500, 520-6000, 520-6500, 520-7000, 520-8000, 520-9000,520-10000, 540-560, 540-580, 540-600, 540-620, 540-640, 540-660,540-680, 540-700, 540-800, 540-900, 540-1000, 540-1500, 540-2000,540-3000, 540-3500, 540-4000, 540-4500, 540-5000, 540-5500, 540-6000,540-6500, 540-7000, 540-8000, 540-9000, 540-10000, 560-580, 560-600,560-620, 560-640, 560-660, 560-680, 560-700, 560-800, 560-900, 560-1000,560-1500, 560-2000, 560-3000, 560-3500, 560-4000, 560-4500, 560-5000,560-5500, 560-6000, 560-6500, 560-7000, 560-8000, 560-9000, 560-10000,580-600, 580-620, 580-640, 580-660, 580-680, 580-700, 580-800, 580-900,580-1000, 580-1500, 580-2000, 580-3000, 580-3500, 580-4000, 580-4500,580-5000, 580-5500, 580-6000, 580-6500, 580-7000, 580-8000, 580-9000,580-10000, 600-620, 600-640, 600-660, 600-680, 600-700, 600-800,600-900, 600-1000, 600-1500, 600-2000, 600-3000, 600-3500, 600-4000,600-4500, 600-5000, 600-5500, 600-6000, 600-6500, 600-7000, 600-8000,600-9000, 600-10000, 620-640, 620-660, 620-680, 620-700, 620-800,620-900, 620-1000, 620-1500, 620-2000, 620-3000, 620-3500, 620-4000,620-4500, 620-5000, 620-5500, 620-6000, 620-6500, 620-7000, 620-8000,620-9000, 620-10000, 640-660, 640-680, 640-700, 640-800, 640-900,640-1000, 640-1500, 640-2000, 640-3000, 640-3500, 640-4000, 640-4500,640-5000, 640-5500, 640-6000, 640-6500, 640-7000, 640-8000, 640-9000,640-10000, 660-680, 660-700, 660-800, 660-900, 660-1000, 660-1500,660-2000, 660-3000, 660-3500, 660-4000, 660-4500, 660-5000, 660-5500,660-6000, 660-6500, 660-7000, 660-8000, 660-9000, 660-10000, 680-700,680-800, 680-900, 680-1000, 680-1500, 680-2000, 680-3000, 680-3500,680-4000, 680-4500, 680-5000, 680-5500, 680-6000, 680-6500, 680-7000,680-8000, 680-9000, 680-10000, 700-800, 700-900, 700-1000, 700-1500,700-2000, 700-3000, 700-3500, 700-4000, 700-4500, 700-5000, 700-5500,700-6000, 700-6500, 700-7000, 700-8000, 700-9000, 700-10000, 800-900,800-1000, 800-1500, 800-2000, 800-3000, 800-3500, 800-4000, 800-4500,800-5000, 800-5500, 800-6000, 800-6500, 800-7000, 800-8000, 800-9000,800-10000, 900-1000, 900-1500, 900-2000, 900-3000, 900-3500, 900-4000,900-4500, 900-5000, 900-5500, 900-6000, 900-6500, 900-7000, 900-8000,900-9000, 900-10000, 1000-1500, 1000-2000, 1000-3000, 1000-3500,1000-4000, 1000-4500, 1000-5000, 1000-5500, 1000-6000, 1000-6500,1000-7000, 1000-8000, 1000-9000, 1000-10000, 1500-2000, 1500-3000,1500-3500, 1500-4000, 1500-4500, 1500-5000, 1500-5500, 1500-6000,1500-6500, 1500-7000, 1500-8000, 1500-9000, 1500-10000, 2000-3000,2000-3500, 2000-4000, 2000-4500, 2000-5000, 2000-5500, 2000-6000,2000-6500, 2000-7000, 2000-8000, 2000-9000, 2000-10000, 2500-3000,2500-3500, 2500-4000, 2500-4500, 2500-5000, 2500-5500, 2500-6000,2500-6500, 2500-7000, 2500-8000, 2500-9000, 2500-10000, 3000-3500,3000-4000, 3000-4500, 3000-5000, 3000-5500, 3000-6000, 3000-6500,3000-7000, 3000-8000, 3000-9000, 3000-10000, 3500-4000, 3500-4500,3500-5000, 3500-5500, 3500-6000, 3500-6500, 3500-7000, 3500-8000,3500-9000, 3500-10000, 4000-4500, 4000-5000, 4000-5500, 4000-6000,4000-6500, 4000-7000, 4000-8000, 4000-9000, 4000-10000, 4500-5000,4500-5500, 4500-6000, 4500-6500, 4500-7000, 4500-8000, 4500-9000,4500-10000, 5000-5500, 5000-6000, 5000-6500, 5000-7000, 5000-8000,5000-9000, 5000-10000, 5500-6000, 5500-6500, 5500-7000, 5500-8000,5500-9000, 5500-10000, 6000-6500, 6000-7000, 6000-8000, 6000-9000,6000-10000, 6500-7000, 6500-8000, 6500-9000, 6500-10000, 7000-8000,7000-9000, 7000-10000, 8000-9000, 8000-10000, or 9000-10000 hr*ng/mL. Insome cases, the AUC_(Last) of the antiarrhythmic pharmaceutical agentadministered via inhalation can be from about 200 to about 2000hr*ng/mL. In some cases, the AUC_(Last) of the antiarrhythmicpharmaceutical agent administered via inhalation can be from about 500to about 800 hr*ng/mL. In some cases, the AUC_(Last) of theantiarrhythmic pharmaceutical agent administered via inhalation can befrom about 400 to about 600 hr*ng/mL. In one or more embodimentsantiarrhythmic pharmaceutical agent is a class I, class II, class III,or class IV antiarrhythmic. In some embodiments, the antiarrhythmicpharmaceutical agent is a class Ic, antiarrhythmic. In otherembodiments, the antiarrhythmic pharmaceutical agent is flecainide or apharmaceutically acceptable salt thereof.

In some cases, the AUC_(Last) can be calculated as the area under theconcentration-time curve up to the last measurable concentration. Insome cases, the AUC_(Last) can be calculated as the total drug exposureover time. In some cases, the AUC_(Last) can be calculated from plasmaconcentration of the antiarrhythmic pharmaceutical agent measured in theleft ventricular chamber. In some cases, the AUC_(Last) can becalculated from plasma concentration of the antiarrhythmicpharmaceutical agent measured in the pulmonary artery. In some cases,the AUC_(Last) can be calculated from plasma concentration of theantiarrhythmic pharmaceutical agent measured in the vein (e.g., femoralvein). In some cases, the AUC_(Last) can be measured in a human PK/PDstudy.

In some cases, the distribution t_(1/2) of the antiarrhythmicpharmaceutical agent administered via inhalation can be from about 0.1minute to about 15 minutes, such as from about 0.1-0.5, 0.1-1, 0.1-1.5,0.1-2, 0.1-2.5, 0.1-2.6, 0.1-2.7, 0.1-2.8, 0.1-2.9, 0.1-3, 0.1-3.1,0.1-3.2, 0.1-3.3, 0.1-3.4, 0.1-3.5, 0.1-3.6, 0.1-3.7, 0.1-3.8, 0.1-3.9,0.1-4, 0.1-4.1, 0.1-4.2, 0.1-4.3, 0.1-4.4, 0.1-4.5, 0.1-5, 0.1-5.5,0.1-6, 0.1-7, 0.1-8, 0.1-9, 0.1-10, 0.1-11, 0.1-12, 0.1-13, 0.1-14,0.1-15, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-2.6, 0.5-2.7, 0.5-2.8,0.5-2.9, 0.5-3, 0.5-3.1, 0.5-3.2, 0.5-3.3, 0.5-3.4, 0.5-3.5, 0.5-3.6,0.5-3.7, 0.5-3.8, 0.5-3.9, 0.5-4, 0.5-4.1, 0.5-4.2, 0.5-4.3, 0.5-4.4,0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 0.5-11,0.5-12, 0.5-13, 0.5-14, 0.5-15, 1-1.5, 1-2, 1-2.5, 1-2.6, 1-2.7, 1-2.8,1-2.9, 1-3, 1-3.1, 1-3.2, 1-3.3, 1-3.4, 1-3.5, 1-3.6, 1-3.7, 1-3.8,1-3.9, 1-4, 1-4.1, 1-4.2, 1-4.3, 1-4.4, 1-4.5, 1-5, 1-5.5, 1-6, 1-7,1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1.5-2, 1.5-2.5, 1.5-2.6,1.5-2.7, 1.5-2.8, 1.5-2.9, 1.5-3, 1.5-3.1, 1.5-3.2, 1.5-3.3, 1.5-3.4,1.5-3.5, 1.5-3.6, 1.5-3.7, 1.5-3.8, 1.5-3.9, 1.5-4, 1.5-4.1, 1.5-4.2,1.5-4.3, 1.5-4.4, 1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-7, 1.5-8, 1.5-9,1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-14, 1.5-15, 2-2.5, 2-2.6, 2-2.7,2-2.8, 2-2.9, 2-3, 2-3.1, 2-3.2, 2-3.3, 2-3.4, 2-3.5, 2-3.6, 2-3.7,2-3.8, 2-3.9, 2-4, 2-4.1, 2-4.2, 2-4.3, 2-4.4, 2-4.5, 2-5, 2-5.5, 2-6,2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 2-13, 2-14, 2-15, 2.5-2.6, 2.5-2.7,2.5-2.8, 2.5-2.9, 2.5-3, 2.5-3.1, 2.5-3.2, 2.5-3.3, 2.5-3.4, 2.5-3.5,2.5-3.6, 2.5-3.7, 2.5-3.8, 2.5-3.9, 2.5-4, 2.5-4.1, 2.5-4.2, 2.5-4.3,2.5-4.4, 2.5-4.5, 2.5-5, 2.5-5.5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10,2.5-11, 2.5-12, 2.5-13, 2.5-14, 2.5-15, 2.6-2.7, 2.6-2.8, 2.6-2.9,2.6-3, 2.6-3.1, 2.6-3.2, 2.6-3.3, 2.6-3.4, 2.6-3.5, 2.6-3.6, 2.6-3.7,2.6-3.8, 2.6-3.9, 2.6-4, 2.6-4.1, 2.6-4.2, 2.6-4.3, 2.6-4.4, 2.6-4.5,2.6-5, 2.6-5.5, 2.6-6, 2.6-7, 2.6-8, 2.6-9, 2.6-10, 2.6-11, 2.6-12,2.6-13, 2.6-14, 2.6-15, 2.7-2.8, 2.7-2.9, 2.7-3, 2.7-3.1, 2.7-3.2,2.7-3.3, 2.7-3.4, 2.7-3.5, 2.7-3.6, 2.7-3.7, 2.7-3.8, 2.7-3.9, 2.7-4,2.7-4.1, 2.7-4.2, 2.7-4.3, 2.7-4.4, 2.7-4.5, 2.7-5, 2.7-5.5, 2.7-6,2.7-7, 2.7-8, 2.7-9, 2.7-10, 2.7-11, 2.7-12, 2.7-13, 2.7-14, 2.7-15,2.8-2.9, 2.8-3, 2.8-3.1, 2.8-3.2, 2.8-3.3, 2.8-3.4, 2.8-3.5, 2.8-3.6,2.8-3.7, 2.8-3.8, 2.8-3.9, 2.8-4, 2.8-4.1, 2.8-4.2, 2.8-4.3, 2.8-4.4,2.8-4.5, 2.8-5, 2.8-5.5, 2.8-6, 2.8-7, 2.8-8, 2.8-9, 2.8-10, 2.8-11,2.8-12, 2.8-13, 2.8-14, 2.8-15, 2.9-3, 2.9-3.1, 2.9-3.2, 2.9-3.3,2.9-3.4, 2.9-3.5, 2.9-3.6, 2.9-3.7, 2.9-3.8, 2.9-3.9, 2.9-4, 2.9-4.1,2.9-4.2, 2.9-4.3, 2.9-4.4, 2.9-4.5, 2.9-5, 2.9-5.5, 2.9-6, 2.9-7, 2.9-8,2.9-9, 2.9-10, 2.9-11, 2.9-12, 2.9-13, 2.9-14, 2.9-15, 3-3.1, 3-3.2,3-3.3, 3-3.4, 3-3.5, 3-3.6, 3-3.7, 3-3.8, 3-3.9, 3-4, 3-4.1, 3-4.2,3-4.3, 3-4.4, 3-4.5, 3-5, 3-5.5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12,3-13, 3-14, 3-15, 3.1-3.2, 3.1-3.3, 3.1-3.4, 3.1-3.5, 3.1-3.6, 3.1-3.7,3.1-3.8, 3.1-3.9, 3.1-4, 3.1-4.1, 3.1-4.2, 3.1-4.3, 3.1-4.4, 3.1-4.5,3.1-5, 3.1-5.5, 3.1-6, 3.1-7, 3.1-8, 3.1-9, 3.1-10, 3.1-11, 3.1-12,3.1-13, 3.1-14, 3.1-15, 3.2-3.3, 3.2-3.4, 3.2-3.5, 3.2-3.6, 3.2-3.7,3.2-3.8, 3.2-3.9, 3.2-4, 3.2-4.1, 3.2-4.2, 3.2-4.3, 3.2-4.4, 3.2-4.5,3.2-5, 3.2-5.5, 3.2-6, 3.2-7, 3.2-8, 3.2-9, 3.2-10, 3.2-11, 3.2-12,3.2-13, 3.2-14, 3.2-15, 3.3-3.4, 3.3-3.5, 3.3-3.6, 3.3-3.7, 3.3-3.8,3.3-3.9, 3.3-4, 3.3-4.1, 3.3-4.2, 3.3-4.3, 3.3-4.4, 3.3-4.5, 3.3-5,3.3-5.5, 3.3-6, 3.3-7, 3.3-8, 3.3-9, 3.3-10, 3.3-11, 3.3-12, 3.3-13,3.3-14, 3.3-15, 3.4-3.5, 3.4-3.6, 3.4-3.7, 3.4-3.8, 3.4-3.9, 3.4-4,3.4-4.1, 3.4-4.2, 3.4-4.3, 3.4-4.4, 3.4-4.5, 3.4-5, 3.4-5.5, 3.4-6,3.4-7, 3.4-8, 3.4-9, 3.4-10, 3.4-11, 3.4-12, 3.4-13, 3.4-14, 3.4-15,3.5-3.6, 3.5-3.7, 3.5-3.8, 3.5-3.9, 3.5-4, 3.5-4.1, 3.5-4.2, 3.5-4.3,3.5-4.4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-7, 3.5-8, 3.5-9, 3.5-10,3.5-11, 3.5-12, 3.5-13, 3.5-14, 3.5-15, 3.6-3.7, 3.6-3.8, 3.6-3.9,3.6-4, 3.6-4.1, 3.6-4.2, 3.6-4.3, 3.6-4.4, 3.6-4.5, 3.6-5, 3.6-5.5,3.6-6, 3.6-7, 3.6-8, 3.6-9, 3.6-10, 3.6-11, 3.6-12, 3.6-13, 3.6-14,3.6-15, 3.7-3.8, 3.8-3.9, 3.8-4, 3.8-4.1, 3.8-4.2, 3.8-4.3, 3.8-4.4,3.8-4.5, 3.8-5, 3.8-5.5, 3.8-6, 3.8-7, 3.8-8, 3.8-9, 3.8-10, 3.8-11,3.8-12, 3.8-13, 3.8-14, 3.8-15, 3.9-4, 3.9-4.1, 3.9-4.2, 3.9-4.3,3.9-4.4, 3.9-4.5, 3.9-5, 3.9-5.5, 3.9-6, 3.9-7, 3.9-8, 3.9-9, 3.9-10,3.9-11, 3.9-12, 3.9-13, 3.9-14, 3.9-15, 4-4.1, 4-4.2, 4-4.3, 4-4.4,4-4.5, 4-5, 4-5.5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14,4-15, 4.1-4.2, 4.1-4.3, 4.1-4.4, 4.1-4.5, 4.1-5, 4.1-5.5, 4.1-6, 4.1-7,4.1-8, 4.1-9, 4.1-10, 4.1-11, 4.1-12, 4.1-13, 4.1-14, 4.1-15, 4.2-4.3,4.2-4.4, 4.2-4.5, 4.2-5, 4.2-5.5, 4.2-6, 4.2-7, 4.2-8, 4.2-9, 4.2-10,4.2-11, 4.2-12, 4.2-13, 4.2-14, 4.2-15, 4.3-4.4, 4.3-4.5, 4.3-5,4.3-5.5, 4.3-6, 4.3-7, 4.3-8, 4.3-9, 4.3-10, 4.3-11, 4.3-12, 4.3-13,4.3-14, 4.3-15, 4.4-4.5, 4.4-5, 4.4-5.5, 4.4-6, 4.4-7, 4.4-8, 4.4-9,4.4-10, 4.4-11, 4.4-12, 4.4-13, 4.4-14, 4.4-15, 4.5-5, 4.5-5.5, 4.5-6,4.5-7, 4.5-8, 4.5-9, 4.5-10, 4.5-11, 4.5-12, 4.5-13, 4.5-14, 4.5-15,5-5.5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, 5-15, 5.5-6,5.5-7, 5.5-8, 5.5-9, 5.5-10, 5.5-11, 5.5-12, 5.5-13, 5.5-14, 5.5-15,6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 7-8, 7-9, 7-10, 7-11,7-12, 7-13, 7-14, 7-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-14, 8-15, 9-10,9-11, 9-12, 9-13, 9-14, 9-15, 10-11, 10-12, 10-13, 10-14, 10-15, 11-12,11-13, 11-14, 11-15, 12-13, 12-14, 12-15, 13-14, 13-15, or 14-15 min. Insome cases, the distribution t_(1/2) of the antiarrhythmicpharmaceutical agent administered via inhalation can be from about 3 toabout 5 minutes. In one or more embodiments antiarrhythmicpharmaceutical agent is a class I, class II, class III, or class IVantiarrhythmic. In some embodiments, the antiarrhythmic pharmaceuticalagent is a class Ic, antiarrhythmic. In other embodiments, theantiarrhythmic pharmaceutical agent is flecainide or a pharmaceuticallyacceptable salt thereof.

In some cases, the distribution t_(1/2) can be calculated as the time atwhich the antiarrhythmic pharmaceutical agent plasma levels decreased tohalf of what they were at equilibrium due to distribution to tissuesthroughout the body. In some cases, the distribution t_(1/2) can becalculated as the time it takes for an antiarrhythmic pharmaceuticalagent to lose half of its pharmacologic activity. In some cases, thedistribution t_(1/2) can be calculated from plasma concentration of theantiarrhythmic pharmaceutical agent measured in the left ventricularchamber. In some cases, the distribution t_(1/2) can be calculated fromplasma concentration of the antiarrhythmic pharmaceutical agent measuredin the pulmonary artery. In some cases, the distribution t_(1/2) can becalculated from plasma concentration of the antiarrhythmicpharmaceutical agent measured in the vein (e.g., femoral vein). In somecases, the distribution t_(1/2) can be measured in a human PK/PD study.

In some cases, the elimination t_(1/2) of the antiarrhythmicpharmaceutical agent administered via inhalation can be from about 1hour to about 25 hours, such as from about 1-3, 1-5, 1-7, 1-7.5, 1-8,1-8.5, 1-8.7, 1-8.9, 1-9.1, 1-9.3, 1-9.5, 1-9.7, 1-9.9, 1-10.1, 1-10.3,1-10.5, 1-10.7, 1-10.9, 1-11.1, 1-11.3, 1-11.5, 1-11.7, 1-11.9, 1-12.1,1-12.5, 1-13, 1-13.5, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-25,3-5, 3-7, 3-7.5, 3-8, 3-8.5, 3-8.7, 3-8.9, 3-9.1, 3-9.3, 3-9.5, 3-9.7,3-9.9, 3-10.1, 3-10.3, 3-10.5, 3-10.7, 3-10.9, 3-11.1, 3-11.3, 3-11.5,3-11.7, 3-11.9, 3-12.1, 3-12.5, 3-13, 3-13.5, 3-14, 3-15, 3-16, 3-17,3-18, 3-19, 3-20, 3-25, 5-7, 5-7.5, 5-8, 5-8.5, 5-8.7, 5-8.9, 5-9.1,5-9.3, 5-9.5, 5-9.7, 5-9.9, 5-10.1, 5-10.3, 5-10.5, 5-10.7, 5-10.9,5-11.1, 5-11.3, 5-11.5, 5-11.7, 5-11.9, 5-12.1, 5-12.5, 5-13, 5-13.5,5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-25, 7-7.5, 7-8, 7-8.5,7-8.7, 7-8.9, 7-9.1, 7-9.3, 7-9.5, 7-9.7, 7-9.9, 7-10.1, 7-10.3, 7-10.5,7-10.7, 7-10.9, 7-11.1, 7-11.3, 7-11.5, 7-11.7, 7-11.9, 7-12.1, 7-12.5,7-13, 7-13.5, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-25, 7.5-8,7.5-8.5, 7.5-8.7, 7.5-8.9, 7.5-9.1, 7.5-9.3, 7.5-9.5, 7.5-9.7, 7.5-9.9,7.5-10.1, 7.5-10.3, 7.5-10.5, 7.5-10.7, 7.5-10.9, 7.5-11.1, 7.5-11.3,7.5-11.5, 7.5-11.7, 7.5-11.9, 7.5-12.1, 7.5-12.5, 7.5-13, 7.5-13.5,7.5-14, 7.5-15, 7.5-16, 7.5-17, 7.5-18, 7.5-19, 7.5-20, 7.5-25, 8-8.5,8-8.7, 8-8.9, 8-9.1, 8-9.3, 8-9.5, 8-9.7, 8-9.9, 8-10.1, 8-10.3, 8-10.5,8-10.7, 8-10.9, 8-11.1, 8-11.3, 8-11.5, 8-11.7, 8-11.9, 8-12.1, 8-12.5,8-13, 8-13.5, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20, 8-25, 8.5-8.7,8.5-8.9, 8.5-9.1, 8.5-9.3, 8.5-9.5, 8.5-9.7, 8.5-9.9, 8.5-10.1,8.5-10.3, 8.5-10.5, 8.5-10.7, 8.5-10.9, 8.5-11.1, 8.5-11.3, 8.5-11.5,8.5-11.7, 8.5-11.9, 8.5-12.1, 8.5-12.5, 8.5-13, 8.5-13.5, 8.5-14,8.5-15, 8.5-16, 8.5-17, 8.5-18, 8.5-19, 8.5-20, 8.5-25, 8.7-8.9,8.7-9.1, 8.7-9.3, 8.7-9.5, 8.7-9.7, 8.7-9.9, 8.7-10.1, 8.7-10.3,8.7-10.5, 8.7-10.7, 8.7-10.9, 8.7-11.1, 8.7-11.3, 8.7-11.5, 8.7-11.7,8.7-11.9, 8.7-12.1, 8.7-12.5, 8.7-13, 8.7-13.5, 8.7-14, 8.7-15, 8.7-16,8.7-17, 8.7-18, 8.7-19, 8.7-20, 8.7-25, 8.9-9.1, 8.9-9.3, 8.9-9.5,8.9-9.7, 8.9-9.9, 8.9-10.1, 8.9-10.3, 8.9-10.5, 8.9-10.7, 8.9-10.9,8.9-11.1, 8.9-11.3, 8.9-11.5, 8.9-11.7, 8.9-11.9, 8.9-12.1, 8.9-12.5,8.9-13, 8.9-13.5, 8.9-14, 8.9-15, 8.9-16, 8.9-17, 8.9-18, 8.9-19,8.9-20, 8.9-25, 9.1-9.3, 9.1-9.5, 9.1-9.7, 9.1-9.9, 9.1-10.1, 9.1-10.3,9.1-10.5, 9.1-10.7, 9.1-10.9, 9.1-11.1, 9.1-11.3, 9.1-11.5, 9.1-11.7,9.1-11.9, 9.1-12.1, 9.1-12.5, 9.1-13, 9.1-13.5, 9.1-14, 9.1-15, 9.1-16,9.1-17, 9.1-18, 9.1-19, 9.1-20, 9.1-25, 9.3-9.5, 9.3-9.7, 9.3-9.9,9.3-10.1, 9.3-10.3, 9.3-10.5, 9.3-10.7, 9.3-10.9, 9.3-11.1, 9.3-11.3,9.3-11.5, 9.3-11.7, 9.3-11.9, 9.3-12.1, 9.3-12.5, 9.3-13, 9.3-13.5,9.3-14, 9.3-15, 9.3-16, 9.3-17, 9.3-18, 9.3-19, 9.3-20, 9.3-25, 9.5-9.7,9.5-9.9, 9.5-10.1, 9.5-10.3, 9.5-10.5, 9.5-10.7, 9.5-10.9, 9.5-11.1,9.5-11.3, 9.5-11.5, 9.5-11.7, 9.5-11.9, 9.5-12.1, 9.5-12.5, 9.5-13,9.5-13.5, 9.5-14, 9.5-15, 9.5-16, 9.5-17, 9.5-18, 9.5-19, 9.5-20,9.5-25, 9.7-9.9, 9.7-10.1, 9.7-10.3, 9.7-10.5, 9.7-10.7, 9.7-10.9,9.7-11.1, 9.7-11.3, 9.7-11.5, 9.7-11.7, 9.7-11.9, 9.7-12.1, 9.7-12.5,9.7-13, 9.7-13.5, 9.7-14, 9.7-15, 9.7-16, 9.7-17, 9.7-18, 9.7-19,9.7-20, 9.7-25, 9.9-10.1, 9.9-10.3, 9.9-10.5, 9.9-10.7, 9.9-10.9,9.9-11.1, 9.9-11.3, 9.9-11.5, 9.9-11.7, 9.9-11.9, 9.9-12.1, 9.9-12.5,9.9-13, 9.9-13.5, 9.9-14, 9.9-15, 9.9-16, 9.9-17, 9.9-18, 9.9-19,9.9-20, 9.9-25, 10.1-10.3, 10.1-10.5, 10.1-10.7, 10.1-10.9, 10.1-11.1,10.1-11.3, 10.1-11.5, 10.1-11.7, 10.1-11.9, 10.1-12.1, 10.1-12.5,10.1-13, 10.1-13.5, 10.1-14, 10.1-15, 10.1-16, 10.1-17, 10.1-18,10.1-19, 10.1-20, 10.1-25, 10.3-10.5, 10.3-10.7, 10.3-10.9, 10.3-11.1,10.3-11.3, 10.3-11.5, 10.3-11.7, 10.3-11.9, 10.3-12.1, 10.3-12.5,10.3-13, 10.3-13.5, 10.3-14, 10.3-15, 10.3-16, 10.3-17, 10.3-18,10.3-19, 10.3-20, 10.3-25, 10.5-10.7, 10.5-10.9, 10.5-11.1, 10.5-11.3,10.5-11.5, 10.5-11.7, 10.5-11.9, 10.5-12.1, 10.5-12.5, 10.5-13,10.5-13.5, 10.5-14, 10.5-15, 10.5-16, 10.5-17, 10.5-18, 10.5-19,10.5-20, 10.5-25, 10.7-10.9, 10.7-11.1, 10.7-11.3, 10.7-11.5, 10.7-11.7,10.7-11.9, 10.7-12.1, 10.7-12.5, 10.7-13, 10.7-13.5, 10.7-14, 10.7-15,10.7-16, 10.7-17, 10.7-18, 10.7-19, 10.7-20, 10.7-25, 10.9-11.1,10.9-11.3, 10.9-11.5, 10.9-11.7, 10.9-11.9, 10.9-12.1, 10.9-12.5,10.9-13, 10.9-13.5, 10.9-14, 10.9-15, 10.9-16, 10.9-17, 10.9-18,10.9-19, 10.9-20, 10.9-25, 11.1-11.3, 11.1-11.5, 11.1-11.7, 11.1-11.9,11.1-12.1, 11.1-12.5, 11.1-13, 11.1-13.5, 11.1-14, 11.1-15, 11.1-16,11.1-17, 11.1-18, 11.1-19, 11.1-20, 11.1-25, 11.3-11.5, 11.3-11.7,11.3-11.9, 11.3-12.1, 11.3-12.5, 11.3-13, 11.3-13.5, 11.3-14, 11.3-15,11.3-16, 11.3-17, 11.3-18, 11.3-19, 11.3-20, 11.3-25, 11.5-11.7,11.5-11.9, 11.5-12.1, 11.5-12.5, 11.5-13, 11.5-13.5, 11.5-14, 11.5-15,11.5-16, 11.5-17, 11.5-18, 11.5-19, 11.5-20, 11.5-25, 11.7-11.9,11.7-12.1, 11.7-12.5, 11.7-13, 11.7-13.5, 11.7-14, 11.7-15, 11.7-16,11.7-17, 11.7-18, 11.7-19, 11.7-20, 11.7-25, 11.9-12.1, 11.9-12.5,11.9-13, 11.9-13.5, 11.9-14, 11.9-15, 11.9-16, 11.9-17, 11.9-18,11.9-19, 11.9-20, 11.9-25, 12.1-12.5, 12.1-13, 12.1-13.5, 12.1-14,12.1-15, 12.1-16, 12.1-17, 12.1-18, 12.1-19, 12.1-20, 12.1-25, 12.5-13,12.5-13.5, 12.5-14, 12.5-15, 12.5-16, 12.5-17, 12.5-18, 12.5-19,12.5-20, 12.5-25, 13-13.5, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19,13-20, 13-25, 13.5-14, 13.5-15, 13.5-16, 13.5-17, 13.5-18, 13.5-19,13.5-20, 13.5-25, 14-15, 14-16, 14-17, 14-18, 14-19, 14-20, 14-25,15-16, 15-17, 15-18, 15-19, 15-20, 15-25, 16-17, 16-18, 16-19, 16-20,16-25, 17-18, 17-19, 17-20, 17-25, 18-19, 18-20, 18-25, 19-20, 19-25, or20-25 hours. In some cases, the elimination t_(1/2) of theantiarrhythmic pharmaceutical agent administered via inhalation can befrom about 8.5 to about 10.5 hours. In one or more embodimentsantiarrhythmic pharmaceutical agent is a class I, class II, class III,or class IV antiarrhythmic. In some embodiments, the antiarrhythmicpharmaceutical agent is a class Ic, antiarrhythmic. In otherembodiments, the antiarrhythmic pharmaceutical agent is flecainide or apharmaceutically acceptable salt thereof.

In some cases, the elimination t_(1/2) can be calculated as the time atwhich the antiarrhythmic pharmaceutical agent plasma levels decreased tohalf of what they were at equilibrium due to metabolism and elimination.In some cases, the elimination t_(1/2) can be calculated from plasmaconcentration of the antiarrhythmic pharmaceutical agent measured in theleft ventricular chamber. In some cases, the elimination t_(1/2) can becalculated from plasma concentration of the antiarrhythmicpharmaceutical agent measured in the pulmonary artery. In some cases,the elimination t_(1/2) can be calculated from plasma concentration ofthe antiarrhythmic pharmaceutical agent measured in the vein (e.g.,femoral vein). In some cases, the elimination t_(1/2) can be measured ina human PK/PD study.

In some cases, the maximum change in QRS interval duration (ΔQRS)following the antiarrhythmic pharmaceutical agent administered viainhalation can be from about 0.01 msec to about 100 msec, such as fromabout 0.01-0.1, 0.01-0.5, 0.01-1, 0.01-1.5, 0.01-2, 0.01-2.5, 0.01-3,0.01-3.5, 0.01-4, 0.01-4.5, 0.01-5, 0.01-5.5, 0.01-6, 0.01-8, 0.01-10,0.01-15, 0.01-20, 0.01-25, 0.01-30, 0.01-40, 0.01-50, 0.01-60, 0.01-70,0.01-80, 0.01-90, 0.01-100, 0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5,0.1-3, 0.1-3.5, 0.1-4, 0.1-4.5, 0.1-5, 0.1-5.5, 0.1-6, 0.1-8, 0.1-10,0.1-15, 0.1-20, 0.1-25, 0.1-30, 0.1-40, 0.1-50, 0.1-60, 0.1-70, 0.1-80,0.1-90, 0.1-100, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4,0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-8, 0.5-10, 0.5-15, 0.5-20, 0.5-25,0.5-30, 0.5-40, 0.5-50, 0.5-60, 0.5-70, 0.5-80, 0.5-90, 0.5-100, 1-1.5,1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1-5.5, 1-6, 1-8, 1-10, 1-15,1-20, 1-25, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1.5-2,1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-8,1.5-10, 1.5-15, 1.5-20, 1.5-25, 1.5-30, 1.5-40, 1.5-50, 1.5-60, 1.5-70,1.5-80, 1.5-90, 1.5-100, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5, 2-5, 2-5.5, 2-6,2-8, 2-10, 2-15, 2-20, 2-25, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90,2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 2.5-5.5, 2.5-6, 2.5-8,2.5-10, 2.5-15, 2.5-20, 2.5-25, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70,2.5-80, 2.5-90, 2.5-100, 3-3.5, 3-4, 3-4.5, 3-5, 3-5.5, 3-6, 3-8, 3-10,3-15, 3-20, 3-25, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100,3.5-4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-8, 3.5-10, 3.5-15, 3.5-3.20,3.5-3.25, 3.5-3.30, 3.5-40, 3.5-50, 3.5-60, 3.5-70, 3.5-80, 3.5-90,3.5-100, 4-4.5, 4-5, 4-5.5, 4-6, 4-8, 4-10, 4-15, 4-20, 4-25, 4-30,4-40, 4-50, 4-60, 4-70, 4-80, 4-90, 4-100, 4.5-5, 4.5-5.5, 4.5-6, 4.5-8,4.5-10, 4.5-15, 4.5-20, 4.5-25, 4.5-30, 4.5-4.50, 4.5-50, 4.5-60,4.5-70, 4.5-80, 4.5-90, 4.5-100, 5-5.5, 5-6, 5-8, 5-10, 5-15, 5-20,5-25, 5-30, 5-40, 5-50, 5-60, 5-70, 5-80, 5-90, 5-100, 5.5-6, 5.5-8,5.5-10, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 5.5-40, 5.5-50, 5.5-60, 5.5-70,5.5-80, 5.5-90, 5.5-100, 6-8, 6-10, 6-15, 6-20, 6-25, 6-30, 6-40, 6-50,6-60, 6-70, 6-80, 6-90, 6-100, 8-10, 8-15, 8-20, 8-25, 8-30, 8-40, 8-50,8-60, 8-70, 8-80, 8-90, 8-100, 10-15, 10-20, 10-25, 10-30, 10-40, 10-50,10-60, 10-70, 10-80, 10-90, 10-100, 15-20, 15-25, 15-30, 15-40, 15-50,15-60, 15-70, 15-80, 15-90, 15-100, 20-25, 20-30, 20-40, 20-50, 20-60,20-70, 20-80, 20-90, 20-100, 25-30, 25-40, 25-50, 25-60, 25-70, 25-80,25-90, 25-100, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 40-50,40-60, 40-70, 40-80, 40-90, 40-100, 50-60, 50-70, 50-80, 50-90, 50-100,60-70, 60-80, 60-90, 60-100, 70-80, 70-90, 70-100, 80-90, 80-100, or90-100 msec. In some cases, the maximum change in QRS interval duration(ΔQRS) following the antiarrhythmic pharmaceutical agent administeredvia inhalation can be from about 1 to about 10 msec. In some cases, themaximum change in QRS interval duration (ΔQRS) following theantiarrhythmic pharmaceutical agent administered via inhalation can befrom about 5 to about 20 msec. In some cases, the ΔQRS can be measuredin a human PK/PD study. In the present disclosure, the term “ΔQRS”, ifnot referred to with reference to time post-administration of theantiarrhythmic agent, can be used interchangeably with the term “maximumΔQRS”, e.g. meaning the maximum change in QRS following administrationof the antiarrhythmic agent as provided herein. In one or moreembodiments antiarrhythmic pharmaceutical agent is a class I, class II,class III, or class IV antiarrhythmic. In some embodiments, theantiarrhythmic pharmaceutical agent is a class Ic, antiarrhythmic. Inother embodiments, the antiarrhythmic pharmaceutical agent is flecainideor a pharmaceutically acceptable salt thereof.

In some cases, the time point at which the QRS interval is measuredfollowing the antiarrhythmic pharmaceutical agent administration viainhalation to determine the ΔQRS relative to pre-dose can be from about0.1 minute to about 450 minutes, such as from about 0.1-1, 0.1-3, 0.1-5,0.1-10, 0.1-15, 0.1-30, 0.1-45, 0.1-60, 0.1-90, 0.1-120, 0.1-150,0.1-180, 0.1-210, 0.1-240, 0.1-270, 0.1-300, 0.1-330, 0.1-360, 0.1-390,0.1-410, 0.1-450, 1-3, 1-5, 1-10, 1-15, 1-30, 1-45, 1-60, 1-90, 1-120,1-150, 1-180, 1-210, 1-240, 1-270, 1-300, 1-330, 1-360, 1-390, 1-410,1-450, 3-5, 3-10, 3-15, 3-30, 3-45, 3-60, 3-90, 3-120, 3-150, 3-180,3-210, 3-240, 3-270, 3-300, 3-330, 3-360, 3-390, 3-410, 3-450, 5-10,5-15, 5-30, 5-45, 5-60, 5-90, 5-120, 5-150, 5-180, 5-210, 5-240, 5-270,5-300, 5-330, 5-360, 5-390, 5-410, 5-450, 10-15, 10-30, 10-45, 10-60,10-90, 10-120, 10-150, 10-180, 10-210, 10-240, 10-270, 10-300, 10-330,10-360, 10-390, 10-410, 10-450, 15-30, 15-45, 15-60, 15-90, 15-120,15-150, 15-180, 15-210, 15-240, 15-270, 15-300, 15-330, 15-360, 15-390,15-410, 15-450, 30-45, 30-60, 30-90, 30-120, 30-150, 30-180, 30-210,30-240, 30-270, 30-300, 30-330, 30-360, 30-390, 30-410, 30-450, 45-60,45-90, 45-120, 45-150, 45-180, 45-210, 45-240, 45-270, 45-300, 45-330,45-360, 45-390, 45-410, 45-450, 60-90, 60-120, 60-150, 60-180, 60-210,60-240, 60-270, 60-300, 60-330, 60-360, 60-390, 60-410, 60-450, 90-120,90-150, 90-180, 90-210, 90-240, 90-270, 90-300, 90-330, 90-360, 90-390,90-410, 90-450, 120-150, 120-180, 120-210, 120-240, 120-270, 120-300,120-330, 120-360, 120-390, 120-410, 120-450, 150-180, 150-210, 150-240,150-270, 150-300, 150-330, 150-360, 150-390, 150-410, 150-450, 180-210,180-240, 180-270, 180-300, 180-330, 180-360, 180-390, 180-410, 180-450,210-240, 210-270, 210-300, 210-330, 210-360, 210-390, 210-410, 210-450,240-270, 240-300, 240-330, 240-360, 240-390, 240-410, 240-450, 270-300,270-330, 270-360, 270-390, 270-410, 270-450, 300-330, 300-360, 300-390,300-410, 300-450, 330-360, 330-390, 330-410, 330-450, 360-390, 360-410,360-450, 390-410, 390-450, or 410-450 min.

The antiarrhythmic activity of pharmaceutical agent can be correlatedwith QRS interval duration. In some examples, the antiarrhythmicpharmaceutical agent administered via inhalation can have higherantiarrhythmic activity as compared to the antiarrhythmic pharmaceuticalagent administered by intravenous delivery (e.g., intravenous infusion).In some cases, such a higher antiarrhythmic activity is reflected by ahigher ratio of maximum ΔQRS to C_(max). For example, given the sameC_(max), e.g., peak plasma concentration of the antiarrhythmicpharmaceutic agent, inhalation delivery of the antiarrhythmic agent asprovided herein can have a higher maximum ΔQRS as compared tointravenous delivery of the same agent. In some cases, the comparisonmay not be made between corresponding doses via the two differentadministration routes, for example, inhalation of a first dose of theagent can have a first C_(max) (C_(max1)) and a first maximum ΔQRS(ΔQRS_(max1)), and intravenous administration of a second dose of theagent can have a second C_(max) (C_(max2)) and a second maximum ΔQRS(ΔQRS_(max2)). In some cases, C_(max1) and C_(max2) can be similar. Inother case, C_(max1) and C_(max2) can be dissimilar. In some examples ofthe present disclosure, the ratio of ΔQRS_(max1) versus C_(max1) can behigher than ΔQRS_(max2) versus C_(max2), i.e.,ΔQRS_(max1)/C_(max1)>ΔQRS_(max2)/C_(max2). In some cases,ΔQRS_(max1)/C_(max1) is at least 1.1 folds, at least 1.2 folds, at least1.3 folds, at least 1.4 folds, at least 1.5 folds, at least 1.6 folds,at least 1.7 folds, at least 1.8 folds, at least 1.9 folds, at least 2.0folds, at least 2.1 folds, at least 2.2 folds, at least 2.3 folds, atleast 2.4 folds, at least 2.5 folds, at least 2.6 folds, at least 2.7folds, at least 2.8 folds, at least 2.9 folds, at least 3.0 folds, atleast 3.1 folds, at least 3.2 folds, at least 3.3 folds, at least 3.4folds, at least 3.5 folds, at least 3.6 folds, at least 3.7 folds, atleast 3.8 folds, at least 3.9 folds, at least 4.0 folds, at least 4.2folds, at least 4.4 folds, at least 4.6 folds, at least 4.8 folds, atleast 5.0 folds, at least 5.5 folds, at least 6 folds, at least 7 folds,at least 8 folds, at least 9 folds, at least 10 folds, at least 12folds, at least 15 folds, at least 20 folds, at least 25 folds, or atleast 50 folds greater than ΔQRS_(max2)/C_(max2). In some cases,ΔQRS_(max1)/C_(max1) is at least 2 folds greater thanΔQRS_(max2)/C_(max2). In one or more embodiments antiarrhythmicpharmaceutical agent is a class I, class II, class III, or class IVantiarrhythmic. In some embodiments, the antiarrhythmic pharmaceuticalagent is a class Ic, antiarrhythmic. In other embodiments, theantiarrhythmic pharmaceutical agent is flecainide or a pharmaceuticallyacceptable salt thereof.

The present invention will be further illustrated by way of thefollowing Examples. These examples are non-limiting and do not restrictthe scope of the invention. Unless stated otherwise, all percentages,parts, etc. presented in the examples are by weight.

EXAMPLES Example 1 Prophetic Analytical Model Involving Verapamil andLidocaine

Published pharmacokinetic and pharmacodynamic models (FIG. 4 ) showrelationships between drug concentration in coronary blood and desiredcoronary effect. IV drug information was used from published literature.HARRISON et al., “Effect of Single Doses of Inhaled Lignocaine on FEV1and Bronchial Reactivity in Asthma,” Respir Med., 12:1359-635 (December1992). Inhaled drug information was simulated based on known propertiesof pulmonary small molecule absorption.

FIG. 5 shows the different time concentration profiles of drugadministered via the IV and inhalation routes. Verapamil was selected asan example heart drug as it possesses both cardiac rate and rhythmcontrol properties and is often used to rescue acute arrhythmia episodes(e.g., PSVT, paroxysmal supraventricular tachycardia).

FIG. 6 also shows different time concentration profiles of drugadministered via the IV and inhalation routes. Lidocaine was selected asan example heart drug. This PK/PD modeling with lidocaine shows samehigh feasibility.

Example 2 Effects of Intratracheal (IT) Administration ofAnti-Arrhythmic Compounds on the Ventricular Response of Dogs withInduced Atrial Fibrillation and Supraventricular Tachycardia (SVT)

Objective:

To evaluate the effects/efficacy of common antiarrhythmic drugs whengiven via the pulmonary route, on the electrophysiological response ofanesthetized dogs with induced atrial fibrillation and supraventriculartachycardia.

Animal Models Used

Atrial Fibrillation Model:

Anesthesia/Surgical Preparation:

A venous catheter was placed in a peripheral vessel (i.e., cephalic) foradministration of anesthetic. For anesthesia induction, all animals weregiven morphine sulfate (˜2 mg/kg) and a bolus of alpha chloralose (˜100mg/kg) intravenously through the venous catheter. Anesthesia wassustained with alpha chloralose (35-75 mg/kg/hour IV), until completionof the study (<2 hours). Following induction, animals wereendotracheally intubated and mechanically ventilated (˜12 breaths/minutewith a tidal volume of 200-300 mL). Subsequently, a cut-down on ajugular vein permitted introduction of a pacing lead into the rightatrium. Transthoracic electrodes forming ECG lead II were placed. Fortest/vehicle article delivery, a 4F catheter was introduced through thetrachea and wedged into a small airway, and a venous catheter was placedin a peripheral vessel (i.e., cephalic).

Experiments:

Following instrumentation and hemodynamic stabilization (for at least 15minutes), phenylephrine was continuously infused (2 ug/kg/min IV) toelevate the systemic arterial pressure and increase vagal(parasympathetic) efferent activity for the duration of the study.Approximately 5 min after administration of this parasympathomimetic wasstarted; the following experiments were performed:

First, the right atrium was paced (20 V, 40 Hz, 4 ms pulse) for 15minutes, and following pacing discontinuation, atrial fibrillationensued. Approximately 3 minutes after pacing was stopped and atrialfibrillation was observed, the animals were given vehicle (˜3 mL)intra-tracheally (IT); the duration between dosing and, (if observed)the return to sinus rhythm and/or the ventricular rate was noted.Observations were made for up to 10 minutes.

Subsequently, atrial fibrillation was re-established via 15-minutepacing cycle(s), as described above. Once pacing was discontinued andatrial fibrillation was observed/stable for 3 minutes, the animals wereadministered the vehicle or one of the test articles, delivered as abolus (˜3 mL) directly into a small airway through the intratrachealcatheter. Vehicle was only water. In the case of flecainide as the testarticle, the concentration was 15 mg of flecainide/3 ml of water.Following dosing, the duration between cessation of administration and,if observed, return to sinus rhythm and/or ventricular rate were noted;observations were made for up to 10 minutes. Overall, threegroups/test-articles were studied, and up to two animals were assignedto each group (n=2/group): one group received flecainide acetate (2-4mg/kg, FLE), while the others received diltiazem (0.25-0.50 mg/kg, DIL)or dofetilide (20-60 ug/kg, DOF); only one test article was administeredper animal. The experimental protocol(s) are summarized in FIG. 7 .

Supraventricular Tachycardia Model:

Anesthesia/Surgical Preparation:

A venous catheter was placed in a peripheral vessel (i.e., cephalic) foradministration of anesthetic(s). For anesthesia induction, all animalswere given a combination of diazepam (˜0.5 mg/kg) and ketamine (˜10mg/kg) intravenously through this venous catheter. Anesthesia wassustained until completion of the study with an intravenous infusion ofpentobarbital (5-15 mg/kg/hr). Following induction, animals wereendotracheally intubated and mechanically ventilated (˜12 breaths/minwith a tidal volume of 200-300 mL).

Subsequently, a cut-down on a jugular vein permitted the introduction ofa pacing lead into the right atrium. Similarly, for arterial pressuremonitoring, a solid-state micromanometer catheter (Millar Instruments)was advanced into the aortic root via a cut-down over an artery (e.g.,femoral, carotid). Transthoracic electrodes forming ECG lead II wasplaced. For vehicle/test article delivery, a 4F catheter was introducedthrough the trachea and wedged into a small airway, and a venouscatheter was placed in a peripheral vessel (i.e., cephalic).

Experiments:

Following instrumentation/hemodynamic stabilization (for at least 15minutes), right atrial pacing (5-10 V, 40 Hz, 2 ms pulses) wasestablished in order to induce supraventricular tachycardia (SVT);pacing and SVT was sustained throughout the duration of the experiments.Approximately 5 minutes after onset of SVT and while monitoringECG/arterial pressure continuously, the animals were administered threeescalating doses (one at a time) of a test article; each dose wasdelivered as a bolus (˜3 mL) directly into a small airway through theintratracheal catheter (IT). Following dosing, the heart-rate (HR) andarterial pressure response were monitored for 15 minutes.

Subsequently (once the response to three IT doses had been recorded),hemodynamic recovery was allowed for approximately 30 minutes, and theelectrocardiographic/hemodynamic response to the highest test-articledose was re-evaluated; however, for comparison purposes, this dose wasdelivered intravenously (IV).

Overall, two groups/test-articles were studied, and up to two animalswere assigned to each group (n=2/group): one group received esmolol HCL(0.5-1.0 mg/kg, ESM), while the other received adenosine (0.25-1.0mg/kg, ADN); only one test article was administered to per animal. Theexperimental protocol(s) are summarized in FIG. 8 .

Observations:

Atrial Fibrillation:

Among the three test articles (flecainide, diltiazem and dofetilide)studied, both flecainide and diltiazem rapidly converted the AtrialFibrillation to normal sinus rhythm, while dofetilide marginally slowedthe ventricular rate.

Vehicle:

FIG. 9 shows a representative example of a dog in atrial fibrillationprior to administration of either vehicle or test article. FIG. 10 showsan example of the vehicle having no effect on the arrhythmia. Vehicleadministered in same volumes as the test articles had no effect on thearrhythmia.

Flecainide:

At pulmonary dose between 2-4 mg/kg body weight, flecainide convertedthe induced atrial fibrillation to normal sinus rhythm. Large doses ofthe drug also resulted in slower ventricular rates. None to minimal dropin mean arterial pressure was noted. Neither dogs exhibited any knownadverse events such as proarrhythmia. See FIGS. 11 and 12 .

Diltiazem:

At pulmonary doses of 0.25 mg/kg body weight, diltiazem converted theinduced atrial fibrillation to normal sinus rhythm and also prolongedthe PQ interval. Heart rate also slowed down but marginally. There washowever a notable drop in mean arterial blood pressure (MAP). See FIG.13 .

Dofetilide:

At escalating pulmonary doses of 10-40 mcg/kg body weight, dofetilidecaused minor reduction in heart rate.

Supraventricular Tachycardia (SVT):

Diltiazem:

The diltiazem delivered via the pulmonary and IV routes were comparablein all aspects. The Mean Arterial Pressure (MAP) dropped significantlyin both cases, attributed directly to the dose of the drug. Diltiazemalso prolonged the PR interval indicating that the drug delivered byeither IV or pulmonary routes has the potential to convert the SVT tonormal sinus rhythm. The timing of the electrophysiological change wascomparable between IV and pulmonary. See FIGS. 14 and 15 .

Esmolol:

Elevating doses of esmolol were shown to produce 2^(nd) degree AV blockat lower doses and also prolonging the PR intervals in the ECG traces.See FIGS. 16-20 .

However, higher doses of esmolol at 1.0 mg/kg did not produce the sameelectrophysiological effects. It is noteworthy that esmolol deliveredvia the lung did not cause a drop in MAP in any of the doses.

Adenosine:

Adenosine administered via the lung did not have any effect on theheart. Adenosine is known to metabolize differently in different speciesand it is not clear whether the effect was due to the ultra-rapidmetabolism of adenosine or the model not being sensitive enough.

SUMMARY

There was a clear cardiovascular effect of diltiazem, flecainide, and aprobable effect of esmolol and dofetilide when given by intratrachealinstillation. These drugs comprise four divergent classes of chemicaland pharmacological agents. Although a clear response was not observedwith adenosine, it is still considered worthy of evaluation in otheranimal models. The responses mimicked qualtitatively those of the IVroute and known physiological effects of all test articles fordiltiazem, flecainide, and esmolol. There may be some physical orphysicochemical property of adenosine that precludes absorption from thetracheal route in this animal model. Additionally, administration into asingle small airway would not be expected to produce the same exposureas administration by inhalation where the surface for diffusion would bemany orders of magnitude greater.

These studies confirm the physiological effects of divergent chemicalson cardiovascular function. The intratracheal route of administrationpossesses 3 potential advantages. (1) It is the shortest route frompoint of administration to the target organ—the heart. (2) There is lessdilution therefore a higher concentration to the target organ would beexpected. (3) There would be a reduction in metabolism (i.e., first passeffect) since there is no organ (e.g., liver) for metabolizing betweensite of administration and target organ.

Example 3 Preliminary Evaluation of Solubility and Taste ofAntiarrhythmic Pharmaceutical Agents when Administered as an Aerosol

Objective:

To evaluate the solubilities of flecainide acetate and diltiazemhydrochloride in water and to evaluate the acceptability of taste andaftertaste of these two drugs for administration as liquid aerosols.

Experiment and Observations Preformulation Studies

Diltiazem's solubility was >90 mg/mL at room temperature. The pH of a3.5 mg/mL solution of diltiazem in water was 6.7. At 50 mg/mL, adiltiazem in water solution was about 80% to isotonic.

Flecainide's solubility was about 30 mg/mL at room temperature. The pHof a 2.6 mg/mL solution of flecainide in water was 5.0. At 30 mg/mL, aflecainide in water solution was about 50% to isotonic.

The following solution strengths were prepared for taste evaluation: (1)diltiazem hydrochloride—50 mg/ml solution in distilled water; and (2)flecainide acetate—30 mg/ml solution in distilled water. The solutionswere clear with no visible particulate matter.

Inhalation Device:

The Aeroneb®GO device was used because it is a simple-to-use devicedeveloped specifically for patients who require respiratory therapy inand away from the home. The device can be used by patients of all ages(infant through adult) and aerosolizes solutions intended forinhalation. Aeroneb® Go works with either an AC wall controller or abattery pack, and can be cleaned with soap and water.

Inhalation Procedure:

Volunteers:

Number of subjects: 2 healthy male volunteers

Volunteer-1: age—48

Volunteer-2: age—63

Nebulizer Testing:

Water was poured into the nebulizer cup, and the nebulizer was turnedon. The visible cloud of aerosol generated when the nebulizer was turnedon was treated as a qualitative aerosol standard.

Flecainide Acetate:

About 1 ml of the 30 mg/ml solution was poured into the cup of thenebulizer. The nebulizer was turned on and the resulting aerosol wassimilar to but not as dense as the aerosol formed with the water alone.

The nebulizer was then placed in the mouth and switched on. Deep lunginhalation was performed through the nebulizer. About 40 μl (˜1.2 mg offlecainide acetate) of the test solution was inhaled. The inhaled dosewas sub-therapeutic in nature as it was much less than the regular 100mg administered as tablets. Flecainide acetate is also available as anIV injection in Europe as 10 mg/ml strength in 15 ml ampoules.

Diltiazem Hydrochloride:

About 1 ml of the 50 mg/ml solution was poured into the cup of thenebulizer. The nebulizer was turned on and the resulting aerosol wassimilar to but not as dense as the aerosol formed with the water alone.

The nebulizer was then placed in the mouth and a switched on. Deep lunginhalation was performed through the nebulizer. About 40 μl (˜2 mg ofdiltiazem hydrochloride) of the test solution was inhaled. The inhaleddose was sub-therapeutic in nature as it was much less than the IVinjection marketed in the U.S. as 5 mg/ml in 5 ml vials.

Conclusions and Observations

1. The visible aerosol characteristics test solutions were similar toeach other but not as dense as the water.

2. Flecainide acetate: The taste feedback from both volunteers was verysimilar.

a. Taste: Mildly bitter taste felt in the back of the tongue

b. Aftertaste: There was none to little aftertaste 5 minutes after theinhalation maneuver.

3. Diltiazem hydrochloride: Water was inhaled to wash out any of theflecainide residues. The taste feedback from both volunteers was verysimilar.

a. Taste: Mildly bitter taste felt in the back of the tongue

b. Aftertaste: There was none to little aftertaste 5 minutes after theinhalation maneuver.

4. Other observations:

a. No burning sensations was felt in the mouth, throat, or lungs

b. No visible adverse events were observed. Both volunteers rested for60 minutes after dosing.

Example 4 A Single Ascending Dose Study of Flecainide Acetate InhalationSolution to Assess the Safety, Tolerability, Pharmacokinetics andPharmacodynamics of the Drug

A Phase 1 study was performed in normal healthy volunteers to assess thesafety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) oforal inhaled flecainide and to compare the PK/PD relationship of inhaledflecainide acetate solution to intravenous (IV) flecainide acetate. ThePhase 1 clinical study (FLE-001) was a single center study conducted atCMAX in Adelaide, Australia, comprised of two parts (sub-studies), PartA and Part B. The 1) pharmacokinetics (PK), 2) pharmacodynamics (PD),and 3) safety and tolerability of single ascending doses (SADs) ofinhaled flecainide acetate compared to placebo in healthy volunteerswere evaluated.

Study Design:

This was a single-center study comprising two parts, A and B. The studydesign schematic is shown in FIG. 21 .

Part A was a double-blind, randomized, placebo-controlled designconsisting of SADs of flecainide acetate inhalation solution (estimatedtotal lung doses [eTLD] of 20 mg, 40 mg, or 60 mg) or matching placeboinhalation solution administered using a hand-held inhaler device(AeroEclipse® II Breath Actuated Nebulizer (BAN)) to healthy adult malesand females. Subjects were randomized to receive a single inhalation ofeither flecainide acetate inhalation solution or placebo inhalationsolution in double-blind fashion. 3 cohorts of subjects, in total 34healthy adult volunteers, were recruited for Part A study.

Part B was an open label non-randomized crossover in a cohort of 6evaluable healthy adult volunteers. This part of the study consisted oftwo periods with each subject receiving a total of 2 doses offlecainide, one dose in each period. In Period 1, 3 subjects receivedflecainide acetate solution by inhalation at the dose level of 30 mgeTLD, and 3 subjects received a single dose of 2 mg/kg (or 150 mg,whichever is less) via a 10 min intravenous (IV) infusion of flecainide(Tambocor™ Injection; approved and used in clinical practice inAustralia). In Period 2, the subjects who received flecainide inhalationsolution in Period 1 now received a single dose of IV flecainide (2mg/kg or 150 mg, whichever is less, via a 10 min infusion), while thesubjects who received IV flecainide in Period 1 now received flecainideinhalation solution (30 mg eTLD). Shown in FIGS. 87A and 87B are thebaseline (pre-dose) values of HR, Systolic BP and Diastolic BP (FIG.87A) and, PR and QRS interval durations (FIG. 87B) for Period 1 andPeriod 2 in the 6 subjects studied (prior to administration offlecainide, either via IV infusion or oral inhalation. The finding thatthe baseline values for Period 1 and Period 2 prior to dosing are nearidentical is consistent with the expectation from a cross-over designstudy. The interpretation that there was no carry over effect oftreatment or other changes in the subjects' vital signs and ECGintervals between the two periods.

Chronologically, experiments involving Cohorts 1, 2, and 5 started inearly stage of this clinical study, while experiments involving subjectsin Cohort 3 started later. As a result, some of the data analysespresented below are based on data from Cohorts 1, 2, and/or 5 withoutdata from Cohorts 3.

Study Population:

In Cohorts 1 and 2, all 22 volunteer subjects were healthy maleCaucasians, except for one Asian.

In Cohort 3, all 12 volunteer subjects were male Caucasians.

In Cohort 5, 7 volunteer subjects were enrolled, among which 6 completedthe study. All subjects were male. Of the 6 volunteer subjects whocompleted the study, 5 were Caucasians and one Asian.

Doses:

Subjects in Cohort 1 (n=8) inhaled placebo (n=2) or 20 mg eTLD of aflecainide acetate solution (n=6). Subjects in Cohort 2 (n=14) inhaledplacebo (n=4) or 40 mg eTLD of a flecainide acetate solution (n=10).Subjects in Cohort 3 (n=12) inhaled placebo (n=3) or 60 mg eTLD of aflecainide acetate solution (n=9). Subjects in Cohort 5 first inhaled 30mg eTLD of a flecainide acetate solution and later received 2 mg/kg offlecainide by IV infusion (n=3), or subjects in Cohort 5 initiallyreceived 2 mg/kg of flecainide by IV infusion and subsequently inhaled30 mg eTLD of a flecainide acetate solution (n=3).

In this study, for inhalation delivery of flecainide, the estimatedtotal lung doses (eTLDs) were calculated to account for losses offlecainide in the inhalation device and losses of flecainide insubjects' mouth and throat. eTLD was thereby used to denote the dosethat actually reached the lungs of the subjects. By design, in allnebulizers there can be a residual volume or mass of drug solution thatstays in the nebulizer, and there can also be a percentage of theaerosol caught by subject's throat and mouth. For instance, in thisstudy, it was estimated that 30% of the aerosol was lost in subject'sthroat and mouth. Therefore the eTLD would be:

eTLD=(100−30)%*amount of aerosolized drug that leftnebulizer=70%*(amount of drug placed in nebulizer−amount of drug stayingin nebulizer).

The percentage of aerosol that is caught by subject's throat and mouthcan depend on the aerosol particle size, for example, the fraction ofthe aerosol that is above approximately 5 microns. The amount thatpasses the throat and gets to the lungs can be termed “Fine ParticleFraction (FPF).”

The amount of drug that stays in the nebulizer can depend on the designof the nebulizer and how it is operated. For example, for some jetnebulizers, this can be about 0.5 to 2 mL of solution. For somevibrating mesh nebulizers, it can be 0.05 to 0.3 mL. For Dry PowderInhalers, it can be 10% to 50% of the dose, etc.

Safety:

Heart rate and systolic and diastolic blood pressure were measuredpre-dose, immediately following oral inhalation or IV infusion ofplacebo or flecainide, and up to 360 minutes after oral inhalation or IVinfusion of placebo or flecainide to evaluate cardiovascular safety.

Pulmonary safety was assessed by performing lung spirometry tests andmeasuring peripheral oxygen saturation (SpO₂%) prior to dosing and atvarious times after completion of the inhalation. Lung spirometry testsevaluated all lung function parameters, including forced vital capacity(FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow(PEF), and forced expiratory flow at 25% and 75% intervals (FEF25-75).Auscultation and respiration rate were also measured prior to dosing andat various times after inhalation. Chest x-rays were performed onsubjects before and after flecainide inhalation.

Adverse events were monitored and recorded.

PK:

Venous plasma concentration of flecainide was measured following oralinhalation or IV infusion (10 min) of flecainide.

The following PK parameters were calculated: the maximum venous plasmaconcentration of flecainide observed (C_(max)), the time at which theC_(max) was observed (T_(max)), the area under the concentration-timecurve up to the last measurable concentration (AUC_(Last)), the time atwhich flecainide plasma levels decreased to half of what they were atequilibrium due to distribution to tissues throughout the body(distribution t_(1/2)), and the time at which flecainide plasma levelsdecreased to half of what they were at equilibrium due to metabolism andelimination (elimination t_(1/2)).

PD:

Intensive electrocardiographic (ECG) monitoring was performed in allsubjects during the study to assess the pharmacodynamic activity (e.g.,QRS intervals) of inhaled or IV administered flecainide. The ECGrecordings included: 1) Continuous real-time ECG telemetry forobservation of patient safety starting at 12 hours pre-dose andcontinuing for 12 hours post-dose, 2) 12-lead ECGs for immediate reviewby medical staff to ascertain the safety of the procedures and drugadministration were recorded at pre-specified (or any time as needed)before dosing (pre-dose) and after dosing (post-dose), and 3) continuous12-lead ECG (cECG, iCardiac Holter monitoring) was recorded for 24hours, starting 1 hour prior to dosing and up to 24 hours post dosing.

Results:

Safety Evaluations:

The changes in heart rate (HR), arterial systemic blood pressure (BP),and pulmonary function test parameters associated with administration offlecainide or placebo were assessed. In addition, the effects ofchanging posture from semi-recumbent to seated upright, vice-versa andduring inhalation on HR and BP were assessed (Cohort 5).

Transient increases (between 1 and 3 minutes) in both HR and systolicand diastolic BPs were observed in subjects administered inhaledflecainide and placebo. These changes can be attributed to thesympathetic reflex (unloading of baroreceptors) responses to posturalchanges (from semi-recumbent to seated) and likely to the oralinhalation procedure, e.g., the relatively prolonged and deeprespiratory breath, akin to ˜2 seconds of breath-holding at the end ofinspiratory phase of the inhalation.

Heart Rate Measurements:

The magnitude of the increases in HR was variable, not dose-dependent(e.g., greater increases in the 20 mg eTLD than in the 30, 40 and 60 mgeTLD groups). The baseline HR in beats per minute (bpm) was within theexpected range for the population of healthy subjects in Cohort 1.Immediately, at the end of inhalation of 20 mg eTLD of flecainideacetate, there was an initial increase in HR from baseline with meanchange-from-baseline heart rate (ΔHR) of ˜12 bpm at 1 and 3 minutes,with subsequently smaller increases at later time points. Fifteen and 30minutes after the end of inhalation, mean ΔHR was ˜4 bpm (FIG. 22 ).

In subjects of Cohort 2, there was an initial transient increase in theHR of 12 to 8 bpm at 1 to 3 minutes, respectively, after completion ofinhalation of 40 mg eTLD of flecainide. Thereafter, the HR quicklydecreased toward the pre-dose; at 10 minutes, post-dosing ΔHR was +5 bpm(FIG. 23 ).

The time course of the changes in HR in subjects of Cohort 3 that weregiven either flecainide (eTLD of 60 mg) or placebo inhalation solutionsare shown in FIG. 72 . For 60 mg eTLD (FIG. 72 ) the changes in heartrate (HR) were comparable to those observed in the placebo group.

An increase in HR was observed in subjects of Cohort 5 following singledose administration of inhaled flecainide (30 mg eTLD) and IV flecainide(2 mg/kg) (FIG. 24 ).

There was no change in HR following the inhalation of the placebosolution.

Systolic and Diastolic Blood Pressure Measurements:

During inhalation of either flecainide acetate or placebo solutions,both systolic and diastolic blood pressure (BP) of subjects in Cohort 1increased during the first 15 minutes (placebo) to 30 minutes(flecainide) after completion of the inhalation. Thereafter, theydeclined toward the pre-dose pressures (FIGS. 25A and B).

During inhalation of either flecainide (40 mg eTLD) or placebo, bothsystolic and diastolic pressures in subjects of Cohort 2 rosetransiently during the initial 1 to 3 minutes and declined towardpre-dose values within the following 10 to 15 minutes after completionof the inhalation (FIGS. 26A and B).

In the subjects of cohort 3, those that inhaled the highest eTLD of 60mg, the increases in systolic and diastolic BP at or near the time(T_(max)) of maximal (peak) concentration (C_(max)) of flecainideachieved, were 5 and 4 mmHg, respectively; whereas for subjects thatinhaled the placebo solution, the increases were 3 and 2 mmHg,respectively.

Considering the overlapping standard deviations of the mean values, themagnitude of the changes in blood pressure (systolic and diastolic), forsubjects receiving either inhaled flecainide or placebo, were similarfor all doses tested.

Increases in systolic and diastolic BP were observed in subjects ofCohort 5 following single dose administration of inhaled flecainide (30mg eTLD; FIGS. 27A and B). Decreases in systolic and diastolic BP wereobserved following IV flecainide administration (2 mg/kg; FIGS. 27A andB).

Further analyses are shown in FIG. 73 with regards to changes in HR andblood pressures after IV flecainide or inhaled flecainide. The maximalincrease in HR with administration of IV infusion of flecainide was 7bpm, at the end of infusion (FIG. 73 ). The increases in HR during andfollowing the IV infusion of flecainide were accompanied by a transientdecrease in systolic pressure of 9 mmHg at the end of infusion (FIG. 73) and as much as 18 mmHg at 3 minutes post-dosing (FIG. 75A). Diastolicpressure decreased by ˜2 mmHg at the end of infusion (not shown) and byas much as 7 mmHg at 3 minutes post-dosing (FIG. 75B). The maximalincrease in HR with administration of inhaled flecainide was 5 bpm, atthe end of inhalation (FIG. 74 ). During oral inhalation of flecainide,the HR at 1 minute after completion of inhalation (duration ofinhalation ˜4.5 minutes) increased by 2 bpm (FIG. 74 ). Not shown atmid-point (1.5 minutes) into the inhalation, the HR, which was highlyvariable among subjects, increased from 68±12 to 77±17 bpm (data notavailable for 4 of 6 subjects). The changes in systolic (FIGS. 74 and75A) and diastolic (FIG. 75B) pressures were rather small, in the rangeof −3 to +1 mmHg. For the administration via inhalation, the changes,increases or decreases, in HR and BP can be attributed, in part, to thechange in posture and/or inhalation procedure (FIGS. 72, 75A and 75B).For the IV infusion, the transient decrease in BP can be attributed tothe negative ionotropic effects of flecainide, whereas the increase inHR is due to the baroreceptor reflex triggered by the fall in BP. FIGS.75A and 75B summarize the changes in systolic (FIG. 75A) and diastolicblood (FIG. 75B) pressures following administration of IV infusion ororal inhalation of flecainide, and it shows a lack of negativehemodynamic effects of inhaled flecainide at an eTLD of 30 mg comparedto the ˜5-fold higher dose (˜150 mg) of flecainide given via IVinfusion.

Lung Spirometry Measurements:

For all the subjects in Cohorts 1, 2, 3, and 5, all standard lungspirometry measurements (e.g., FEV1, PEF, FVC and FEF 25-75) andperipheral 02 saturation values were normal before and after flecainideor placebo. Likewise, there were minimal or no changes in respiratoryrate. There were no differences among cohorts or between randomizedtreatment assignment.

The results of the lung spirometry tests performed in subjects of Cohort1 are summarized in Table 1 below.

TABLE 1 Changes in pulmonary function parameters of subjects from Cohort1 prior to and following oral inhalation of flecainide acetate (20 mgeTLD) and placebo solutions. Flecainide (n = 6) Placebo (n = 2) TimeStd. Std. Point Test Unit Mean Dev SEM Mean Dev SEM 12 hours FVC L 6.020.25 0.11 6.17 1.12 0.80 Pre-dose FEV1 L 5.26 1.25 0.51 5.19 0.95 0.67PEF L/s 11.30 1.86 0.76 9.52 0.15 0.11 FEF 25-75 L/s 5.38 2.13 0.87 5.671.05 0.75 3 hours FVC L 6.42 0.96 0.39 6.10 1.44 1.02 Post-dose FEV1 L5.27 1.22 0.50 5.14 1.11 0.78 PEF L/s 10.87 1.88 0.77 10.37 2.34 1.66FEF 25-75 L/s 5.48 1.99 0.81 5.48 0.99 0.70 24 hours FVC L 6.36 0.980.40 6.18 1.31 0.93 Post-dose FEV1 L 5.18 1.27 0.52 5.25 1.03 0.73 PEFL/s 11.09 2.01 0.82 10.70 2.14 1.52 FEF 25-75 L/s 5.40 2.73 1.12 5.690.84 0.59 Abbreviations: FVC = forced vital capacity; FEV1 = forcedexpiratory volume in 1 second; PEF = peak expiratory flow; FEF25-75 =forced expiratory flow at 25% and 75% intervals

The results of the lung spirometry tests performed in subjects of Cohort2 are summarized in Table 2 below.

TABLE 2 Changes in pulmonary function parameters of subjects from Cohort2 prior to and following oral inhalation of flecainide acetate (40 mgeTLD) and placebo solutions Flecainide (n = 10) Placebo (n = 4) TimeStd. Std. Point Test Units Mean Dev SEM Mean Dev SEM 12 hours FVC L 6.180.96 0.32 5.56 0.53 0.26 Pre-dose FEV1 L 5.04 0.74 0.25 4.67 0.56 0.28PEF L/s 10.83 1.73 0.55 9.71 0.91 0.46 FEF25-75 L/s 5.00 0.91 0.29 4.610.95 0.48 3 hours FVC L 6.19 0.72 0.23 5.64 0.56 0.28 Post-dose FEV1 L4.96 0.57 0.18 4.58 0.36 0.18 PEF L/s 10.66 1.94 0.61 9.59 1.28 0.64FEF25-75 L/s 4.34 0.77 0.24 4.51 0.54 0.27 24 hours FVC L 6.39 0.68 0.225.68 0.80 0.40 Post-dose FEV1 L 5.08 0.51 0.16 4.60 0.66 0.33 PEF L/s11.14 1.96 0.62 9.60 1.54 0.77 FEF25-75 L/s 4.80 0.73 0.23 4.60 0.820.41

The pre-dose and post-dose for all lung function parameters (e.g., FVC,FEV1, PEF, and FEF25-75) were within the normal range for the populationstudied, and not different from each other. There were no differencesbetween either cohorts (1 vs 2) or groups (placebo vs flecainide) withineach cohort (Table 1 and Table 2).

Peripheral oxygen saturation measurements: peripheral oxygen saturationlevels measured in subjects of Cohort 1 are summarized in Table 3.

Peripheral oxygen saturation levels measured in subjects of Cohort 2 aresummarized in Table 4.

The pre-dose and post-dose values for SpO₂ were within the normal range(97-98%) and not different from each other. There were minimal or nodifferences in SpO₂% between groups (flecainide vs placebo) and Cohorts(1 vs 2).

Auscultation was normal in all subjects before and after inhalation offlecainide (20 mg eTLD, 30 mg eTLD, 40 mg eTLD) and placebo solutions.

No changes in respiration rate were measured before and after inhalationof flecainide (20 mg eTLD, 30 mg eTLD, 40 mg eTLD) and placebosolutions.

Chest x-rays were normal and showed no changes in subjects before andafter inhalation of flecainide (20 mg eTLD, 30 mg eTLD, 40 mg eTLD) andplacebo solutions.

TABLE 3 Summary of data on peripheral oxygen saturation (SpO₂%) forsubjects of Cohort 1 measured prior to and at various times followinginhalation of flecainide acetate solution (20 mg eTLD) or placebo.Oxygen Saturation (SpO2%) Time Point Mean Std. Dev SEM FlecainidePredose 98 0.82 0.33 (n = 6) 15 min Postdose 97 1.21 0.49 30 minPostdose 97 1.60 0.65 45 min Postdose 97 1.21 0.49 60 min Postdose 970.75 0.31 75 min Postdose 98 0.84 0.34 90 min Postdose 98 0.52 0.21 105min Postdose 97 0.89 0.37 120 min Postdose 98 0.55 0.22 Placebo Predose98 0.71 0.50 (n = 2) 15 min Postdose 97 0.00 0.00 30 min Postdose 971.41 1.00 45 min Postdose 97 0.71 0.50 60 min Postdose 97 0.00 0.00 75min Postdose 98 0.71 0.50 90 min Postdose 98 0.71 0.50 105 min Postdose98 0.71 0.50 120 min Postdose 98 0.71 0.50

TABLE 4 Summary of data on peripheral oxygen saturation (SpO₂%) forsubjects of Cohort 2 measured prior to and at various times followinginhalation of flecainide acetate solution (40 mg eTLD) or placebo.Oxygen Saturation (SpO2%) Time Mean Std. Dev SEM Flecainide Predose 970.79 0.25 (n = 10) 15 min Postdose 96 1.81 0.57 30 min Postdose 97 0.850.27 45 min Postdose 96 0.82 0.26 60 min Postdose 96 0.92 0.29 75 minPostdose 97 1.16 0.37 90 min Postdose 97 0.63 0.20 105 min Postdose 970.88 0.28 120 min Postdose 97 0.52 0.16 Placebo Predose 98 0.50 0.25 (n= 4) 15 min Postdose 98 0.82 0.41 30 min Postdose 98 0.50 0.25 45 minPostdose 98 0.58 0.29 60 min Postdose 98 0.00 0.00 75 min Postdose 980.58 0.29 90 min Postdose 98 0.96 0.48 105 min Postdose 98 0.50 0.25 120min Postdose 98 0.50 0.25

Adverse Events:

In part A of the study, out of 34 subjects studied, 25 were given aflecainide solution via oral inhalation and 9 subjects were given aplacebo solution. There was a total of 66 treatment-emergent adverseevents (TEAEs) in 28 out of 34 subjects (82%). All adverse events weremild and required no treatment.

In study involving Cohorts 1 and 2, the majority of adverse eventslasted between 15-90 minutes. Flecainide was well tolerated, and nosubject interrupted the inhalation. Table 5 below summarizes the mostcommon adverse events reported by subjects in Cohorts 1 and 2.

TABLE 5 Summary of the most common adverse events in subjects followinginhalation of a flecainide acetate solution or placebo solution Cohort 1(n = 8) Cohort 2 (n = 14) Placebo Flecainide Placebo Flecainide AdverseEvent (n = 2) (n = 6) (n = 4) (n = 10) Throat Discomfort/ 0 2 1 5Irritation Lightheadedness 1 1 0 1 Cough 0 1 1 1

A summary of the study-drug related AEs and the assessment of theirintensity is summarized in Table 6. From all 34 subjects studied, 24(71%) had a total of 47 TEAEs that were considered study-drug related.Only 2 (6%) subjects had a total of 3 moderate or severe TEAEs; 1subject (3%) had 2 TEAEs that were considered study-drug related. Noserious adverse events were reported, and no subject had to interruptthe inhalation of the flecainide acetate or placebo solutions.

TABLE 6 Summary of Treatment-Emergent Adverse Events by Treatment byCohort/Inhaled Flecainide Dose Level and Treatment Type: Part A (SafetyPopulation) IH Flecainide Total 20 mg 40 mg 60 mg Flecainide Placebo (N= 6) (N = 10) (N = 9) (N = 25) (N = 9) n (%) n (%) n (%) n (%) n (%)Subjects with at least one: TEAE 4 (67) 10 (100) 8 (89) 22 (88) 6 (67)Study Drug 2 (33) 10 (100) 8 (89) 22 (80) 4 (44) Related^(1, 3) Moderateor Severe² 1 (17) 1 (10) 2 (8) Study Drug Related, 1 (10) 1 (4) Moderateor Severe^(1, 2, 3) SAEs Number of: TEAEs 12  24 23 59 7 Study Drug 7 1917 43 4 Related^(1, 2) Moderate or Severe³ 1 2 3 Study Drug Related, 2 2Moderate or Severe^(1, 2, 3) SAEs Abbreviations: N = number of subjects;SAE = serious adverse event; TEAE = treatment-emergent adverse event;¹Related TEAE = Probable and Possible Related TEAEs; ²Subjects reportingmore than one TEAE were counted only once using the strongest study drugrelationship category; ³subjects reporting more than one TEAE werecounted only once using the highest severity grade.

The majority of TEAEs occur in 1 or 2 subjects each; those occurring in≥2 subjects across all cohorts and receiving either flecainide orplacebo inhalation solution are summarized in Table 7.

The AEs that occurred more frequently in subjects receiving flecainidewere oropharyngeal discomfort, shortness of breath (dyspnoea), cough anddry mouth. However, the incidence of AEs reported by the subjects thatreceived flecainide appears not to be dose-dependent. These AEs wereconsidered mild in intensity and required no treatment. Two moderateadverse events (AEs) were reported by one subject from Cohort #2 (40 mgeTLD); lightheadedness and oropharyngeal discomfort.

Of the 43 total TEAEs in the combined flecainide dose groups, 38 (in19/25 subjects, 76%) and 5 events in 1 subject (4%) were considered tobe probably and possibly study-drug related, respectively. The mostfrequent events in the total flecainide group were (events, subjects andpercentage): Oropharyngeal discomfort: 10 events in 10/25 subjects(40%); Dyspnoea (shortness of breath): 4 events in 4/25 subjects (16%);Dizziness: 3 events in 3/25 subjects (12%); Cough: 3 events in 3/25subjects (12%); Dry mouth: 3 events in 3/25 subjects (12%); Headache: 3events in 2/25 subjects (8%); Dysgeusia: 2 events in 2/25 subjects (8%).

TABLE 7 Summary of Treatment-Emergent Adverse Events in ≥2 Subjects inthe Total Flecainide or Placebo Groups by MedDRA System Organ Class,Preferred Term, Cohort/Inhaled Flecainide Dose Level and Treatment Type:Part A (Safety Population) IH Flecainide Dose Group Total 20 mg 40 mg 60mg IH Flecainide Placebo System Organ Class, (N = 6) (N = 10) (N = 9) (N= 25) (N = 9) Preferred Term n (%) [events] n (%) [events] n (%)[events] n (%) [events] n (%) [events] Nervous system 2 (33) [4] 3 (30)[4] 3 (33) [3]  8 (32) [11] 1 (11) [1] disorders Dizziness 1 (17) [1] 1(10) [1] 1 (11) [1] 3 (12) [3] 1 (11) [1] Dysgeusia 2 (20) [2] 2 (8)[2]  Headache 2 (33) [3] 2 (22) [2] 4 (16) [5] Respiratory, thoracic 3(50) [5]  8 (80) [11] 6 (67) [9] 17 (68) [25] 3 (33) [4] and mediastinaldisorders Cough 1 (17) [2] 1 (10) [1] 1 (11) [1] 3 (12) [4] Dyspnoea 1(17) [1] 3 (30) [3] 2 (22) [2] 6 (24) [6] Oropharyngeal 2 (33) [2] 5(50) [5] 4 (44) [4] 11 (44) [11] 1 (11) [1] discomfort Gastrointestinal3 (30) [3] 5 (56) [8]  8 (32) [11] 2 (22) [2] disorders Diarrhoea 2 (22)[2] 2 (8) [2]  Dry mouth 1 (10) [1] 2 (22) [2] 3 (12) [3] 1 (11) [1]General disorders and 2 (20) [2] 1 (11) [2] 3 (12) [4] administrationsite conditions Catheter site pain 1 (10) [1] 1 (11) [1] 2 (8) [2] Abbreviations: N = number of subjects; SAE = serious adverse event; TEAE= treatment-emergent adverse event; Note: If a subject had more than oneAE coded to the same MedDRA term, the subject was counted only once.

In the pooled placebo group, there were 4 events in 4/9 subjects (44%)deemed possibly or probably related to study-drug; they were thefollowing: oropharyngeal discomfort, respiratory tract irritation,abdominal discomfort, and dry mouth. No TEAEs related to the studydevice were reported.

In Part B of the study, all six subjects had a total of 12 and 49 TEAEsduring inhaltion (IH) and 10 min IV infusion of flecainide,respectively, that is 4-fold fewer TEAEs with IH than IV (Table 8). Allsubjects had at least 1 study-drug-related TEAE. All TEAEs reported bysubjects following inhalation were mild in intensity whereas followingIV infusion, 4 of these in 2 subjects (29%) were considered moderate orsevere (Table 8). There were 1 severe and 2 moderate intensity AEs,probably related to the study drug, reported by the same 6 subjects whenthey received IV infusion of flecainide. The serious AE occurred in asubject in which the IV infusion had to be interrupted for hypotension(systolic BP<65 mmHg) and reported severe light-headedness (dizziness).There were no SAEs reported with either IH or IV flecainideadministration (Table 8).

TABLE 8 Overall Summary of Treatment-Emergent Adverse Events byFlecainide Dosing Route (IH and IV): Part B (Safety Population) IH IV (N= 6) (N = 7) n (%) n (%) Number of Subjects with at least one: TEAE 6(100) 7 (100) Related TEAEs1 6 (100) 7 (100) Moderate or Severe TEAEs³ 02 (29)  Related, Moderate or Severe TEAEs^(1, 2, 3) 0 2 (29)  SAE 0 0Number of Treatment-Emergent Adverse Events 12 49 Related TEAEs¹ 9 35Moderate or Severe TEAEs 0 4 Related, Moderate or Severe TEAEs¹ 0 4 SAEs0 0 Abbreviations: IH = inhaled (30 mg eTLD inhaled flecainide); IV =intravenous (2 mg/kg intravenous flecainide [Tambacor] to a maximum doseof 150 mg); N = number of subjects; SAE = serious adverse event; TEAE =treatment emergent adverse event; ¹Related TEAE = Probable and PossibleRelated TEAEs; ²Subjects reporting more than one TEAE were counted onlyonce using the strongest study drug relationship category; ³Subjectsreporting more than one TEAE were counted only once using the highestseverity grade.

The majority of the TEAEs occurred in 1 or 2 subjects each; thoseoccurring in ≥2 subjects that received either flecainide via oralinhalation (IH) or IV infusion are summarized in Table 9. All subjectsexperienced at least 1 TEAE in each dosing condition (IH and IV);however, as already pointed out, there were 4-fold fewer TEAEsassociated with IH administration compared with IV: 12 events in 6subjects (average of 2 events per subject), versus 49 events in 7subjects (average of 7 events per subject), respectively.

The most frequent TEAEs associated with IV infusion of flecainide werethe following: dizziness (6 events in 6/7 subjects, 86%) and headache (6events in 5/7 subjects, 71%). Also, oral paraesthesia, occurred only inconjunction with IV infusion in 3 subjects (43%). Three events ofperipheral coldness and chest discomfort in 2 and 1 subject each, and 2events in 2 subjects each of application site coldness, catheter sitepain, chest discomfort, and fatigue were also associated with IVinfusion.

TABLE 9 Summary of Treatment-Emergent Adverse Events in ≥2 TotalSubjects by MedDRA System Organ Class, Preferred Term, and FlecainideDosing Route (IH and IV) (Part B) Safety Population IH IV System OrganClass, (N = 6) (N = 7) Preferred Term n (%) [events] n (%) [events]Nervous system disorders  7 (100) [13] Dizziness 6 (86) [6] Headache 5(71) [6] Vascular disorders 3 (43) [4] Peripheral coldness 2 (29) [3]Respiratory, thoracic and 5 (83) [7] 2 (29) [3] mediastinal disordersOropharyngeal discomfort 4 (67) [4] Gastrointestinal disorders 1 (17)[1] 5 (71) [6] Hypoaesthesia oral 1 (17) [1] 1 (14) [1] Paraesthesiaoral 3 (43) [3] General disorders and 2 (33) [2]  4 (57) [13]administration site conditions Application site coldness 2 (29) [2]Catheter site pain 2 (29) [2] Chest discomfort 2 (33) [2] 1 (14) [3]Fatigue 2 (29) [2] Abbreviations: IH = inhaled (30 mg eTLD inhaledflecainide); IV = intravenous (2 mg/kg intravenous flecainide [Tambacor]to a maximum dose of 150 mg); N = number of subjects; TEAE =treatment-emergent adverse event; Note: If a subject had more than oneAE coded to the same MedDRA term, the subject was counted only once.

With IH administration of flecainide, oropharyngeal discomfort was themost frequent TEAE occurring in 4 of 4/6 subjects (67%). The only otherTEAE associated with IH administration that occurred in more than 1subject was chest discomfort, in 2 of 2/6 subjects (33%). However, 3such events also occurred in 1 subject in conjunction with IV infusionof flecainide.

Among the TEAEs associated with both IH and IV infusion, 9 such eventsfrom a total of 12, and 35 events from a total of 49, respectively wereconsidered study-drug related. The type of study-drug related eventsassociated with IV infusion of flecainide were the following: dizziness(6 events in 6 subjects), and headache (5 events in 5 subjects), andparesthesia oral (3 events in 3 subjects). Other study-drug relatedevents associated with IV flecainide administration were: peripheralcoldness, palpitations, and chest discomfort, each occurring 2 times 1subject, and 2 occurrences in 2 subjects of application site coldness.

There were 4 probably study-drug related events associated with IHadministration of flecainide; oropharyngeal discomfort in 4 subjects,the remaining 5 study-drug related events for the IH administrationroute all occurred once in 1 subject each. They were cough, dysphonia,dyspnoea, oral hypoesthesia and chest discomfort. No TEAEs wereconsidered to be related to study device.

PK Results:

Initial analyses demonstrated that oral inhalation of flecainide acetatesolution (20 mg eTLD, 30 mg eTLD, or 40 mg eTLD) resulted in venousplasma concentrations of drug that exhibited near dose proportionality(FIG. 28 ).

FIGS. 76A and 76B show plots of the mean plasma flecainide concentrationversus time for the eTLDs of 20, 40 and 60 mg eTLD oral inhalation dosesgenerated per protocol (FIG. 76A) and from post-hoc (FIG. 76B) datasets.In the majority of the subjects (21 of 25 subjects, 84%), followingcompletion of oral inhalation (IH) of flecainide acetate solution, thevenous plasma concentration of drug rose rapidly, within 1 to 3 minutesafter completion of inhalation, and quickly declined. In two subjects,each in the 40 and 60 mg eTLD cohorts, the T_(max) values (e.g., time tooccurrence of the maximum plasma concentration) were greater than 15minutes, (e.g., ranged from 20 min to 4 hours) after the end ofinhalation, and, in addition, the C_(max) (e.g., maximum plasmaconcentration) values were 3-fold lower (see below) than the other 21subjects. Removal of all data from these four subjects from the mainanalysis (e.g., per-protocol) dataset had minimal effect on the rangeand distribution of all pharmacokinetic parameter values. However, theC_(max) of the two subjects (70.9 and 43.5 ng/ml) from the 40 mg eTLDcohort were 3.0-fold lower and for the two subjects (82.3 and 51.3ng/ml) from the 60 mg eTLD cohort were 3.4-fold lower than the meanC_(max) values of the remaining subjects of the respective cohorts.Inclusion of C_(max) data from these subjects markedly increased therange of C_(max) values and consequently, the PD data from thesesubjects were also excluded from subsequent analyses. The dataset thatexcludes these four subjects is referred to as post-hoc dataset (FIG.76B). The data described in the text, presented in the tables andfigures, hereinafter, are from the post-hoc population, which does notinclude data from the four subjects mentioned above.

Table 10 summarizes the estimates of the pharmacokinetic (PK) parametersof flecainide administered via oral inhalation with a rapid distributionphase lasting ˜10-15 minutes (estimated Liza of 3.5-4.2 minutes) andelimination t_(1/2β) of 9-12 hours. The distribution phase andelimination half-life were independent of the doses of flecainide. TheC_(max) and AUC_(Last) were dose-dependent. It is noteworthy that thevenous plasma concentration-time curves for flecainide (eTLDs of 20, 40,or 60 mg eTLD) administered via oral inhalation or via IV infusion aresimilar (see FIGS. 84A and 84B). The great similarity in theconcentration-time profile curves between flecainide delivered via oralinhalation and IV infusion (shown in FIGS. 84A and 84B) indicatescomparable pharmacokinetics by these two routes of administration. Thisfinding is relevant because the IV route of administration of 2 mg/kg(or maximum 150 mg) of flecainide has been established to be safe andhighly efficacious in converting recent onset symptomatic AF into NSR.

Part B study provided comparison of PK profiles between IV flecainideand inhaled flecainide. In subjects of Cohort 5, the venous plasmaconcentration-time curves for inhaled flecainide (30 mg eTLD) weresimilar to those for flecainide administered via IV infusion (2 mg/kg;FIGS. 29A and B). The peripheral venous plasma concentration-time curvesfor flecainide delivered via IV infusion (2 mg/kg over 10 min; totaldose of 149±17 mg) or inhalation (eTLD of 30 mg) are also replotted on adifferent time scale in FIGS. 77A and 77B. Peak plasma concentrations offlecainide (C_(max)) following intravenous administration and inhalationwere 749±308 and 120±70 ng/ml, respectively. The time to C_(max)(T_(max)) for intravenous infusion was between 1 and 60 minutes afterthe end of 10 min infusion, and ≤1 min post-inhalation (Table 11). Themean time to complete the inhalation of 30 mg eTLD of flecainide in thesix subjects was 4.5 min. The summary of the pharmacokinetic parameters(C_(max), Distribution (Lim) and Elimination (Lim) half-lives) arepresented in Table 11. Distribution phase and elimination half-life werenearly identical for intravenous infusion and inhalation: 4.7±01.4 minand 10.0±1.8 hrs, respectively, for intravenous, and 4.3±1.5 min and10.1±2.0 hrs, respectively, for inhalation. Furthermore, thedistribution and elimination half-lives following intravenousadministration in this Phase 1 study were similar to those published inthe literature for intravenous flecainide.

TABLE 10 Summary of PK Values of Flecainide administered via OralInhalation or IV Route of Adminis- T_(max) C_(max) AUC_(Last) Elim.t_(1/2β) Dist. t_(1/2α) ^(#) tration min ng/mL Hr · ng/mL hours minInhaled 1 (1, 3) 95.1 (79) 421 (45) 9.87 (25) 3.86 (34) (20 mg) n = 6Inhaled 1 (0, 1) 173 (47) 685 (26) 9.0 (24) 4.19 (39) (40 mg) n = 8*Inhaled 1 (0, 3) 232 (78) 946 (22) 12.0 (14) 3.47 (17) (60 mg) n = 7*All values for inhaled flecainide are arithmetic mean (CV %) exceptT_(max) values (measured from end of inhalation) which are median (min,max). *Based on PK cut-off criteria of T_(max) ≥ 15 min, data from 2subjects were excluded. ^(#)Data from 1 subject from 20 and 40 mg eTLDcohorts and 3 subjects from the 60 mg eTLD cohort could not beestimated.

To directly compare the PK profiles of flecainide given via IV infusionand oral inhalation, the mean+/−SD plasma flecainide concentration vstime for the IV dose was normalized to 30 mg in order to match the 30 mgeTLD oral inhalation dose. FIG. 29B and FIG. 78 show the comparisonbetween the normalized plasma flecainide concentration of IV infusionand plasma flecainide concentration of inhalation on different timescales, respectively. The resulting concentration-time profile curvesare near-identical, indicating comparable pharmacokinetics by these tworoutes of administration.

TABLE 11 Summary of PK values of Flecainide Administered via IH or IVand from Literature (shaded) Route of T_(max) C_(max) AUC_(last) Dist.t_(1/2) Elim. t_(1/2) administration (min after EOI) (ng/mL) (hr*ng/mL)(min) (hr) IV (2 mg/Kg)   1 (0, 60) 749 (41) 3051 (11) 4.28^(#) (36)10.0 (18) Cohort 5, n = 6 Inhaled (30 mg) 0.5 (0, 1) 120 (59)  487 (20)4.67^(#) (30) 10.1 (20) Cohort 5, n = 6 IV (2 mg/Kg)* 10.0 1644 ± 5344211 ± 456 2.6 ± 0.7 9.3 ± 0.1 n = 3 (Mean ± SEM) EOI = end ofinhalation or infusion All values (from Part B of study, shown in rows1-2) are arithmetic mean (CV %) except T_(max) values which are median(min, max) ^(#)Data front 1 subject in the IH arm and 2 subjects in theIV arm could not be estimated *Tambacor package insert, 2012, Eisai Co.Ltd.

PD Results:

QRS Interval Duration:

There was a small increase of mean ΔQRS (mean change from baseline,pre-dose QRS interval duration) between 1 and 3 minutes after the end offlecainide inhalation in subjects of Cohort 1. FIG. 31 shows the timecourse of the changes in QRS interval duration (ΔQRS) in 6 subjectsfollowing the inhalation of 20 mg eTLD of flecainide and in 2 subjectsfollowing the inhalation of placebo.

There was a transient increase between 1 and 3 minutes post-dosing inthe QRS duration in subjects of Cohort 2 (40 mg eTLD flecainide); in themajority of subjects, the maximal increase in the QRS interval duration(ΔQRS) was observed at 1 minute post-dosing. The changes in QRS intervalduration for the 10 subjects of Cohort 2 that were exposed to inhaledflecainide are depicted in FIG. 32 .

Representative ECG tracings from an individual subject (R222) in Cohort2 who was exposed to inhaled flecainide (40 mg eTLD) acetate solutionare shown in FIG. 33A. The ECG tracings show that the QRS duration(QRSd) increased by 10 msec at 1 minute post-dosing, whereas theamplitude of the R-wave (QRSa) decreased by 400 μV at 3 min post-dosing.The bar graphs summarize the average changes in QRS interval duration(FIG. 33B) and R-wave amplitude (FIG. 33C) of subject R222 recorded fromseveral tracings of ECGs for each time point. The maximal increase induration (˜9 msec) and decrease in amplitude (˜480 μV) of the QRSinterval complexes were transient and statistically significant(p<0.05).

The time course of changes in the QRS interval duration in Cohorts 1, 2,and 3 were all plotted following after completion of inhalation eitherinhalation of flecainide acetate or placebo solutions (FIG. 79 ; onlydata for post-hoc population). The magnitude of QRS prolongation at 1min post-inhalation dosing was minimal (3.0 msec) with the eTLD of 20 mgeTLD, intermediate (8.2 msec) with the 40 mg dose and attained a maximumof 16 msec with the 60 mg eTLD. The magnitude of the maximal QRSwidening achieved following the administration of the three doses were2.9-fold between 20 mg eTLD and 40 mg eTLD, and 4.5-fold between 20 mgeTLD and 60 mg eTLD. Once the maximal QRS interval prolongation wasachieved (1 to 3 minutes, in general), the QRS interval durationdecreased as a function of time; at 30 min after completion ofinhalation, the QRS interval duration returned to near pre-dose levels.At 2, 4, 6, 8 and 24 hours post-inhalation dosing, the QRS intervaldurations, for all subjects of the 3 cohorts, remained unchanged at nearthe pre-dose (baseline) values (range 80 to 90 msec). Subjects whoreceived placebo had minimal changes in QRS interval, at any timepoint.

In Part B study, the time course of the changes in QRS interval durationmeasured from 12-lead ECGs were obtained in the six subjects prior to,during and following flecainide IV infusion (2 mg/kg, administered over10 mins) and inhalation (30 mg eTLD, mean time 4 min). Subjects inCohort 5 demonstrated a marked prolongation of the QRS interval after IVinfusion of flecainide (2 mg/kg) and showed a transient increase in theQRS interval duration between 1 and 3 minutes post-inhalation of 30 mgeTLD of flecainide acetate solution (FIG. 34 ). QRS interval durationdata from Cohort 5 are also shown in FIGS. 80A and 80B. The mean (±SEM)of the maximal increase in QRS interval duration following IV infusionwas 34.2±2.4 msec and following inhalation was 12.4±2.6 msec. Thewidening of the QRS interval duration was transient in both cases butlasted much longer following intravenous (>60 min) compared toinhalation (15-30 min). At 2 hours following the IV infusion the QRsinterval duration was still 12.5 msec longer than baseline (pre-dosevalue of 78±2 msec), and then steadily shortened at 4, 6 and 8 hourspost-dosing. At 24 hours, prior to discharge, the QRS interval durationwas still ˜7 msec longer than the pre-drug baseline value. In 3 of 6subjects the IV infusion of flecainide caused a non-specificintraventricular conduction delay, indicative of excessive prolongationof the QRS interval duration. In contrast, these changes were notobserved in any of the same subjects when flecainide (eTLD of 30 mg) wasgiven via oral inhalation. From 2 to 24 hours, post-inhalation of theeTLD of 30 mg, the QRS interval duration differed by <2 msec from thepre-dose baseline value of 78±2 msec.

PR Interval:

PR interval measurements were also obtained as flecainide is known toprolong the PR interval in a dose-dependent manner.

In subjects of Cohort 1, the PR interval (time elapsed from onset ofatrial depolarization and onset of ventricular depolarization) wasshortened at early time points with mean ΔPR of −6 msec and −4.5 msec at1 and 3 minutes post-dosing, and values smaller than −3.0 msec from 10minutes to 4 hours after dosing (FIG. 30 ).

Data for Cohort 3 subjects inhaling 60 mg eTLD of flecainide or placebosolution are shown in FIG. 81 . There was a ˜5 msec prolongation in thePR interval duration at the early time points (1 to 5 min), and up to 12msec at 10 and 15 minutes following administration of flecainide. Incontrast, following the inhalation of placebo solution, there was a ˜5msec shortening in the PR interval duration for the first 5 min, andthereafter it returned towards the pre-dose values. Minimal or nochanges of the PR interval duration were seen in subjects that inhaled20 or 40 mg eTLD of flecainide. The PR interval durations at 2, 4, 6, 8and 24 hours post-inhalation dosing, from the subjects of all 3 cohorts,were near identical to the baseline (pre-dose) values, that is, in therange of 140 to 150 msec. In all subjects that inhaled the placebosolution (combined cohorts), the PR interval shortened. The relativelysmall or no changes in PR interval observed prior to, during and after(up to 5-10 minutes post-dosing) can be attributed to the confoundingeffects of postural changes and the inhalation procedure itself. Theprotocol required a seated posture during inhalation of flecainide orplacebo solution. The postural changes from semi-recumbent (beforeinhalation) to seated (during inhalation) position triggers asympathetic reflex that leads to a shortening of the PR interval. Thesympathetic reflex-driven PR interval shortening with seated posture isevident in the placebo curve of FIG. 81 . Therefore, the PR intervalshortening associated with upright posture likely negated most of theexpected lengthening of the PR interval in subjects receivingflecainide.

The results of Part B of the Phase 1 study, in which intervalmeasurements were obtained before, during, and after seated position,clearly shows the re-lengthening of the PR interval following inhalationof flecainide after being shortened during the change in subject'sposition from semi-recumbent to seated upright posture of the subjects.FIGS. 82A and 82B show the changes in PR interval duration measured from12-lead ECGs in the six subjects prior to, during and following IVinfusion. Forty-five min prior to administration of flecainide the PRinterval durations were similar being 164±1 msec with IV infusion and165±2.0 msec with inhalation. At the end of the IV infusion offlecainide (FIG. 82A), the PR interval prolonged to 187±6 and remainedprolonged at 60 min post-IV infusion. At 2 hours post-IV infusion, thePR interval was still ˜12 msec longer than the pre-drug baseline valueof 161±3 msec, and thereafter returned toward baseline; at 8 and 24hours the PR interval had fully returned to pre-drug baseline. The ECGchanges in PR interval duration with inhalation were more complexbecause of the effects of postural changes. As shown in FIG. 82B, whenthe subjects changed position from semi-recumbent to seated, the PRinterval duration shortened by 13 msec from the pre-dose value measuredat −45 min. Subsequently, from the start to the end of the inhalation,the PR interval duration prolonged by 12 msec at 5 min after completionof inhalation and then decreased toward the pre-dose values. Theshortening of the PR interval duration following the postural change(from semi-recumbent to seated) can be attributed to an increase insympathetic tone and was consistent with the observed increases in heartrate (FIG. 72 ) and systolic blood pressure. The PR interval at 2 hoursand beyond (4, 6, 8 and 24 hours) post-oral IH flecainide was (160msec), approximately 2 msec longer than the 158.5 msec of the pre-drugbaseline value. In summary, IV infusion and oral inhalation offlecainide were associated with maximal PR interval prolongations of 25msec and 12 msec, respectively.

Fridericia HR Corrected QT (QTcF) Interval:

The QTcF interval changed little in subjects of Cohort 1 followinginhalation of 20 mg eTLD of flecainide, with small mean changes acrosspost-inhalation time points that varied between +4.0 msec and −2.7 msecduring the first 6 hours (FIG. 35 ).

In subjects of Cohorts 2 and 5, ΔQTcF post-inhalation time points varied±4 msec for 40 mg eTLD and 30 mg eTLD inhaled flecainide, respectively.

T-Wave Morphology:

No changes in T-wave morphology were observed following inhalation offlecainide acetate solution (20 mg eTLD, 30 mg eTLD, and 40 mg eTLD).

T-wave notching, which is an abnormality in T-wave morphology, has beenobserved following IV infusion of flecainide (2 mg/kg; FIG. 36 ).

PK-PD Relationship:

The antiarrhythmic efficacy of flecainide can be strongly correlatedwith the widening of the QRS interval. FIG. 83 shows thedose-concentration response relationship, for the post-hoc population inCohorts 1, 2, and 3, of the effects of inhalation of flecainide on theprolongation of the QRS interval duration. The PK-PD relationship shownbelow is based on the non-steady state, peak plasma levels of flecainideand maximal changes in QRS interval durations post-inhalation. Themaximal QRS interval prolongations were 3.5±1.0, 10±1.5, 16±1.4 for theeTLDs of 20, 40 and 60 mg eTLD, respectively.

In Part B of the present study (FLE-001), flecainide was administered insingle doses via either IV infusion (over 10 minutes) and via oralinhalation (˜4.5 min) in the same subjects. Thus, steady-state plasmalevels of flecainide given either via IV or oral inhalation were notachieved. Consequently, the PK-PD relationship described below are basedon the non-steady state, rapidly changing plasma levels of flecainide([Flec]_(plasma)) and changes in QRS interval durations (ΔQRS) measuredat specific times. As expected from non-steady state conditions, andshown in FIGS. 84A and 84B, a temporal dissociation is observed between([Flec]_(plasma)) and ΔQRS. During both the rapid rise and decline(distribution phase) of the plasma concentration of flecainide, thechanges in QRS interval duration lag those of the peripheral venousconcentrations of flecainide. The hysteresis between concentrations andresponses (QRS) applies for both routes of administration, IV andinhalation.

According to results of the early PK studies of flecainide by Conard etal (1984), peripheral venous plasma levels of flecainide “reflectcardiac tissue concentrations of unchanged flecainide”. Hence, as acorollary, the prolongation of the QRS interval duration caused byflecainide can reflect the ventricular myocardium (primarily left)concentrations of flecainide.

Based on the findings shown in FIGS. 84A and 84B, it was sought todetermine the relationship between peak plasma levels of flecainide(C_(max)) and the maximal ΔQRS instead of using the time-matched valuesof both variables. The results of this analysis are shown in FIG. 85 .

The lower dose of flecainide delivered via oral inhalation (eTLD of 30mg) resulted in lower (6.2-fold) maximal plasma levels of flecainidewhen compared to the higher dose delivered via IV infusion (˜150 mg).Likewise, the pharmacodynamic activity of flecainide, reflected bychanges in the QRS interval duration, were accordingly smaller(2.7-fold) following inhalation than IV infusion. Thus, it appears thata 2.3-fold (6.2/2.7) lower plasma concentration of flecainide given byinhalation can cause prolongation of QRS interval duration of magnitudesachieved following a 10 min IV infusion. In keeping with thisinterpretation, as depicted in FIG. 86 , a direct comparison of datafrom the subjects with near-equal ΔQRS (12.0 to 16 msec) followingeither IV infusion or oral inhalation, yielded plasma concentrations of222±23 and 85±40.3 ng/ml, respectively. Thus, a 2.6-fold lower plasmalevel of flecainide achieved following inhalation results in a ΔQRS of14 msec, a QRS interval widening similar to that achieved at 5 min intothe IV infusion of flecainide; equivalent to 1 mg/kg, that is, half ofthe dose administered (FIGS. 84A and 84B).

SUMMARY

The results of this Phase 1 study demonstrated that inhalation doses offlecainide, in the range of 30 to 60 mg eTLD, are safe, well-toleratedand deliver flecainide into the systemic circulation, within 1 to 3minutes after the completion of inhalation, in sufficient amounts toelicit the expected electrophysiological effects of flecainide, such asprolongation of QRS interval. In Part B of the study, head-to-headcomparisons were made between the PK, PD, safety and tolerability of aneTLD of 30 mg of flecainide given via oral inhalation and that of a10-minute IV infusion dose of 2 mg/kg of flecainide (˜150 mg). Inhaledflecainide was compared with IV flecainide because flecainide given viaIV at the approved dose of 2 mg/kg is an established agent for acutepharmacological cardioversion of recent onset atrial fibrillation.Relevant to the potential effectiveness of inhaled flecainide tocardiovert AF is the observation that at the time of conversion ofatrial fibrillation to sinus rhythm by flecainide IV, the venous plasmaflecainide concentrations are in the range of 114 to 742 ng/ml and theincreases in QRS interval duration are in the range of 12 to 30 msec(Crijns H et al, 1988; Suttorp M J et al, 1990; Donovan K D et al,1995). Inhaled flecainide at eTLD≥30 mg was found to yield venous plasmaflecainide concentrations and cause QRS interval prolongation within thesame range reported above for IV, albeit in the lower end of the rangereported to convert atrial fibrillation to sinus rhythm by IVflecainide. Therefore, based on the pharmacokinetics andpharmacodynamics of flecainide reported in the literature, inhaledflecainide at eTLDs ≥30 mg could be effective in converting recent-onsetatrial fibrillation to sinus rhythm within minutes of administration.Compared to the approved IV flecainide dose, the lower doses of inhaledflecainide are likely to be better tolerated and safer.

Example 5 Pharmacokinetic and Pharmacodynamic Effects of IntratrachealInstillation of Flecainide Acetate with Comparison to IntravenousAdministration in Anesthetized Pigs

The PK and PD responses to intratracheal (IT) instillation were comparedwith IV delivery of flecainide in an intact porcine model that has beenpreviously shown to be clinically relevant (Kumar et al 2009).

Experimental Design:

The studies were carried out in male Yorkshire pigs (n=9) weighing36±1.0 kg (mean±SEM). The pigs were pre-anesthetized with telazol (4.7mg/kg, intramuscular) and subsequently further anesthetized usingalpha-chloralose (80 mg/kg, IV bolus, followed by 24 mg/kg/h continuousIV infusion). The animals were intubated and ventilated at a constantrate of 12 breaths/min and tidal volume of 400 ml per stroke.

All catheters were positioned under fluoroscopic guidance. An Orbiterelectrode catheter was placed in the right atrium for recording localatrial electrograms. Ventricular electrograms were obtained using adecapolar electrode catheter positioned in the left ventricle (LV).Arterial blood pressure was continuously monitored from a femoralarterial sheath. Simultaneous blood samples were drawn from the pigtailcatheter positioned in the LV and from a catheter in the jugular vein.Electrograms were monitored using a Prucka CardioLab workstation (GEMedical Systems, Milwaukee, Wis.) from atrial and ventricular sites. ForIT instillation of flecainide acetate solution, a 5 Fr angioplastycatheter that was 1 cm longer than the endotracheal tube was introducedinto the trachea via the endotracheal tube and its tip was positionedunder fluoroscopy at the tracheal carina level.

In the IV infusion experiments, flecainide (2 mg/kg, IV bolus over 2min) was infused via a 7 Fr sheath inserted into the right femoral vein.The RR, PR, QTc, and JTc intervals and QRS duration were measured in sixsequential beats, recorded seconds before each time point.

In the IT instillation experiments, flecainide (2 mL of 0.75 mg/kg or1.5 mg/kg concentrations, IT) was administered in a single “push” of 2to 3 sec via the angioplasty catheter positioned in the endotrachealtube. For example, for a 36 kg pig, a dose of 27 mg/2 mL (0.75 mg/kg) or54 mg/2 mL (1.5 mg/kg) of flecainide solution can be used. The QTinterval was corrected using Bazett's formula (QTc=QT/√RR) and ispresented in this report as the QTc interval.

When more than one dose was tested in a single experiment, a washoutperiod of 30 to 60 min was allowed in order to keep residual levels offlecainide to a minimum before testing the new dose.

For the experiments on the effects of IT instillation of flecainide onduration of AF, the arrhythmia was induced using intrapericardialadministration of acetylcholine (ACh) (1 mL at a concentration of 15mg/mL) followed by burst pacing for 1 min. Flecainide (1.5 mg/kg, IT)was given after 2 min of successful AF induction.

Blood samples were collected from venous circulation and through the LVpigtail catheter in sodium heparin tubes at 0, 2, 5, 10, 15 and 30 minafter the start of IV or IT flecainide. The samples were centrifuged andfrozen at −80° C. until drug level determination was performed using abioanalytical assay method developed by Climax Laboratories, Inc.

Data are reported as means±SEM. Statistical analyses were performedusing the SAS system (9.4) to apply ANOVA with a post-hoc Dunnett'stest. Statistical significance was assumed at p<0.05.

Results:

Pk Responses:

IV Infusion:

Following IV infusion of flecainide (2 mg/kg over 2 min), both LV andvenous plasma levels peaked at 2 min (LV: 5127±849.4 ng/mL, p<0.05;Venous: 4151±1030.0 ng/mL, p<0.05) and progressively declined throughoutthe experiment to lower levels at 30 min (LV: 497±189.5 ng/mL; Venous:519±195.6 ng/mL) (FIG. 39 ).

IT Instillation of 0.75 mg/kg:

Following IT instillation of the lower dose of flecainide (0.75 mg/kg),both LV and venous plasma levels peaked at 2 min (LV: 1916±122.2 ng/mL,p<0.05; Venous: 1688±176.7 ng/mL, p<0.05) and remained significantlyelevated compared to baseline at 5, 10, and 15 min before progressivelydeclining throughout the experiment to lower levels at 30 min (LV:299±28.6 ng/mL; Venous: 341±54.6 ng/mL) (FIG. 40 ).

IT Instillation of 1.5 mg/kg:

Following IT instillation of the higher dose of flecainide (1.5 mg/kg)both LV and venous plasma levels peaked at 2 min (LV: 3308±247.5 ng/mL,p<0.05; Venous: 2808±216.5 ng/mL, p<0.05) and remained significantlyelevated compared to baseline at 5, 10, and 15 min. Venous plasmaremained significantly elevated compared to baseline at 30 min (Venous:676±79.7 ng/mL, p<0.05) while left ventricular chamber plasma did not(LV: 637±69.5 ng/mL) (FIG. 41 ).

PD Responses:

IV Infusion:

Heart Rate:

Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2 min), heartrate was 103±1.9 bpm. After IV flecainide infusion, ANOVA revealed thatheart rate was not significantly altered across 30 min (p=0.9936) (FIG.42 ).

Arterial Blood Pressure:

Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2 min), meanarterial blood pressure was 105±6.7 mmHg. After IV flecainide infusion,ANOVA analysis revealed that mean arterial pressure was notsignificantly altered across 30 min (p=0.8852) (FIG. 43 ).

PR Interval:

Prior to IV infusion of flecainide (2 mg/kg, IV bolus over 2 min), thePR interval was 127±7.8 ms. After IV flecainide administration, ANOVArevealed that the PR interval was not significantly changed across 30min (p=0.5161; FIG. 44 ).

QRS Duration:

Prior to IV infusion of flecainide (2 mg/kg bolus over 2 min), QRSduration was 58±1.9 ms. After IV flecainide administration, QRS durationsignificantly increased to 77±6.2 ms and 76±4.8 ms coincident with peakplasma levels of the drug at 2 min and 5 min, respectively (p<0.05).Thereafter, QRS duration progressively decreased toward the baselinelevels (59±3.0 ms) at 30 min (FIG. 45 ).

QTc Interval:

Prior to IV infusion of flecainide (2 mg/kg bolus over 2 min), the QTcinterval was 442±7.9 ms. After IV flecainide administration, ANOVArevealed that the QTc interval was not significantly changed across 30min (p=0.35; FIG. 46 ).

JTc Interval:

Prior to IV infusion of flecainide (2 mg/kg bolus over 2 min), theduration of the JTc interval was 367±7.4 ms. After IV flecainideadministration, ANOVA revealed that the JTc interval was notsignificantly changed across 30 min (p=0.9686; FIG. 47 ).

IT Instillation of 0.75 mg/kg:

Heart Rate:

Prior to IT instillation of the lower dose of flecainide (0.75 mg/kg),heart rate was 111±6.4 bpm. After IT infusion, ANOVA revealed that heartrate was not significantly altered across 30 min (p=0.9970; FIG. 48 ).

Arterial Blood Pressure:

Prior to the IT instillation of the lower dose of flecainide (2 mL of0.75 mg/kg), mean arterial blood pressure was 111±3.6 mmHg. After IVflecainide infusion, ANOVA analysis revealed that mean arterial pressurewas not significantly altered across 30 min (p=0.9112; FIG. 49 ).

PR Interval:

Prior to the IT instillation of the lower dose of flecainide (2 mL of0.75 mg/kg), the PR interval was 130±5.3 ms. After IT flecainideinstillation, ANOVA revealed that the PR interval was not significantlychanged across 30 min (p=0.9351; FIG. 50 ).

QRS Duration:

Prior to the IT instillation of the lower dose of flecainide (2 mL of0.75 mg/kg), QRS duration was 58±1.8 ms. After instillation, QRSduration significantly increased to 64±1.6 ms and 65±1.7 ms (p<0.05)coincident with peak plasma levels of the drug at 2 and 5 min,respectively. Thereafter, QRS duration progressively decreased towardthe baseline levels (58±0.9 ms) at 30 min (FIG. 51 ).

QTc Interval:

Prior to the IT instillation of the lower dose of flecainide (2 mL of0.75 mg/kg), the QTc interval was 435±12.9 ms. After instillation, ANOVArevealed that QTc was not significantly changed across 30 min (p=0.5505;FIG. 52 ).

JTc Interval:

Prior to the IT instillation of the lower dose of flecainide (2 mL of0.75 mg/kg), the JTc interval was 354±12.0 ms. After IT flecainideadministration, ANOVA revealed that the JTc interval was notsignificantly changed across 30 min (p=0.7605; FIG. 53 ).

IT Instillation of 1.5 mg/kg:

Heart Rate:

Prior to IT instillation of the higher dose of flecainide (1.5 mg/kg),heart rate was 118±13.2 bpm. After IT infusion, ANOVA revealed thatheart rate was not significantly altered across 30 min (p=0.9999; FIG.54 ).

Arterial Blood Pressure:

Prior to IT instillation of the higher dose of flecainide (1.5 mg/kg),mean arterial blood pressure was 108±9.4 mmHg. After IT infusion, ANOVAanalysis revealed that mean arterial pressure was not significantlyaltered across 30 min (p=0.9894; FIG. 55 ).

PR Interval:

Prior to the IT instillation of the higher dose of flecainide (2 mL of1.5 mg/kg), the PR interval was 127±2.3 ms. After instillation, ANOVArevealed that the PR interval was not significantly changed across 30min (p=0.0819; FIG. 56 ).

QRS Duration:

Prior to the intratracheal instillation of the higher dose of flecainide(2 mL of 1.5 mg/kg), QRS duration was 57±0.4 ms. Following ITinstillation of the higher dose of flecainide (1.5 mg/kg), QRS durationsignificantly increased to 68±1.9 ms, 69±2.2 ms, 67±1.7 ms, and 64±1.3ms (p<0.05), coincident with the increase in the plasma level of thedrug at 2 (peak plasma level), 5, 10, and 15 min, respectively.Thereafter, QRS duration progressively decreased toward the baselinelevels (60±0.9 ms) at 30 min (FIG. 57 ).

QTc Interval:

Prior to the IT instillation of the higher dose of flecainide (2 mL of1.5 mg/kg), the QTc interval was 436±7.1 ms. After instillation, ANOVArevealed that the QTc interval was not significantly changed across 30min (p=0.1510; FIG. 58 ).

JTc Interval:

Prior to the IT instillation of the higher dose of flecainide (2 mL of1.5 mg/kg), the JTc interval was 364±11.5 ms. After instillation, ANOVArevealed that the JTc interval was not significantly changed across 30min (p=0.9968; FIG. 59 ).

Duration of Atrial Fibrillation:

At one min after intrapericardial administration of ACh (1 ml of 100mM), burst pacing was performed to initiate AF in the control cohort(FIG. 60 ).

In the absence of flecainide, AF persisted for 11±0.6 min beforespontaneous conversion to sinus rhythm. The data are shown in Table 12below.

TABLE 12 Effects of intratracheal instillation of flecainide (1.5 mg/kg)on AF duration. AF duration Pig #s No drug Flecainide 239 12 3 236 10 4238 12 3 Mean 11 3 SEM 0.6 0.2 p value 0.008992

In the experimental cohort, after ACh and burst-pacing-induced AF, astable period of 2 min of AF was allowed (FIG. 60 ). Then, ITinstillation of the higher dose of flecainide (2 mL of 1.5 mg/kg) wasperformed. AF was converted to sinus rhythm at 3±0.2 min, a reduction of73% in AF duration from the untreated condition (p<0.009; Table 12; FIG.61 ). Importantly, once sinus rhythm was restored by flecainide, norecurrence of AF occurred within the 30-min window of observation.

In a separate study using a porcine model, the effect of the deliveryrate (i.e., slow versus rapid infusion) of IV administered flecainide onthe PK and PD was evaluated. Venous plasma concentrations (FIG. 62A) andthe QRS interval duration (FIG. 62B) varied in response to slow infusion(10 min) compared with rapid infusion (2 min) of IV flecainide.

As shown in FIG. 62C, venous plasma levels of flecainide were positivelycorrelated with QRS duration.

SUMMARY

IT instillation of the antiarrhythmic agent flecainide generated apharmacokinetic profile that was similar to IV infusion of flecainide.

In addition, IT instillation of flecainide altered electrocardiographicparameters in a manner consistent with its pharmacological activity andconducive to conversion of recent-onset AF to sinus rhythm.

Example 6 Accelerated Cardioversion of Atrial Fibrillation to NormalSinus Rhythm by Intratracheal Delivery of Flecainide Acetate in anIntact Porcine Model

The study tested the efficacy of intratracheal (IT) flecainide toconvert atrial fibrillation (AF) to normal sinus rhythm in a largeanimal model that reproducibly induces AF.

Experimental Design:

In closed-chest anesthetized Yorkshire pigs, intrapericardial (IPC)acetylcholine (ACh) (1 mL of 102.5 mM solution) followed by burst pacingreproducibly induced AF (n=6). Catheter placement is shown in FIG. 63 .

At 2 min after AF induction in all 6 animals, IT flecainide (1.5 or 0.75mg/kg) or no drug was randomly administered. After 30-min recovery, thealternate intervention was tested. Times for conversion to normal sinusrhythm were compared.

Results:

Both IT flecainide doses used accelerated conversion of AF to normalsinus rhythm. As shown in FIG. 64 , AF duration correlated withflecainide dose. IT instillation of flecainide (1.5 mg/kg; n=5)accelerated conversion of AF to normal sinus rhythm in 3.4±0.3 min(mean±SEM) compared to 12.3±1.9 min following no drug (p=0.008), ashortening in AF duration of 72%. The lower IT dose of flecainide (0.75mg/kg; n=3) converted AF to normal sinus rhythm in 8.1±1.0 min, reducingAF duration by 50% vs. no-drug (16.2±0.9; p=0.003).

FIG. 65 shows representative electrograms demonstrating AF conversion at5 min after IT flecainide (1.5 mg/kg) compared to no conversion by 10min after no drug.

FIG. 66A illustrates that the plasma concentration of flecainide reachedlevels required for conversion within 10 min after IT flecainide (0.75mg/kg and 1.5 mg/kg).

FIG. 66B depicts the plasma concentrations of flecainide at the time ofconversion of AF to NSR following IT instillation of flecainide (0.75mg/kg and 1.5 mg/kg).

FIG. 67 demonstrates that IT flecainide reduced the dominant frequencyof AF.

SUMMARY

IT flecainide instillation (1.5 mg/kg or 0.75 mg/kg) was 100% effectivein rapidly converting AF to normal sinus rhythm and restored MAP andventricular rate to baseline values.

The basis for this efficacy is likely rapid absorption of the drugthrough the lungs and delivery as a first-pass bolus to the left atriumvia pulmonary veins.

If the present findings can be confirmed in human subjects, flecainidedelivered via inhalation could provide a potential option for therapy ofnew-onset paroxysmal AF.

Example 7 Rapid Cardioversion of Recent-Onset Atrial Fibrillation withPulmonary Delivery of Flecainide in Anesthetized Dogs

The study tested the hypothesis that pulmonary delivery of flecainidevia IT instillation can, within seconds/few minutes of administration,convert AF into normal sinus rhythm in a dog model of stable AF.

Experimental Design:

The study was carried out in anesthetized healthy adult beagle dogs withinduced AF. Acute AF was induced using the combination of phenylephrine(2-10 mg/kg), to increase heterogeneity of atrial refractory periods viaincreased loading and through a baroreceptor-mediated increase inparasympathetic efferent activity, and right atrial burst pacing (40-50Hz for ˜15 min). The AF induced using this method was, in general,stable for more than 30 mins.

After induction of AF, animals were first given vehicle (0.9% NaCl,volume-matched) via IT installation. Later flecainide, at 2 mg/mL boluswas given (<20 sec) via IT at single or cumulative doses of 0.25 to 0.75mg/kg. For comparison purposes, two dogs were given flecainide viaintravenous bolus injection (<20 sec) at single or cumulative doses of0.25 to 0.75 mg/kg.

The cardiac rhythm was monitored prior to, during AF, and up to 10 minpost-dosing and/or until conversion to NSR.

Plasma concentrations of flecainide were measured in the LV and femoralvein at the time of conversion. In some dogs, plasma levels offlecainide were also measured in the pulmonary artery (PA).

Results:

No conversion of AF to NSR was observed in vehicle treated dogs (0/6).

As shown in Table 13 below, IT-delivered flecainide converted AF to NSRin 63±18 sec at a mean dose of 0.79±0.04 mg/kg in 6/6 dogs. At the timeof conversion of AF to NSR, plasma levels of flecainide were ˜2-foldhigher in the LV than in the systemic venous circulation. In 2/2 dogs,IV bolus of flecainide converted AF to NSR in 29 seconds.

TABLE 13 Effects of IT flecainide in the setting of AF on conversiontimes to NSR, and systemic and LV plasma concentration at the time ofconversion. Plasma Time to Concentration² Animal Dose¹ NSR (ng/mL) Route# (mg/kg) (sec) LV Venous IT 001 0.75 (0.25 + 0.5) 147 538 421 002 0.75(0.25 + 0.5) 52 1140 533  003* 0.75 12 3105 1670 004 0.75 23 700 219 0050.75 62 351 109 006  1.0 (0.75 + 0.25) 83 1000 717 Mean ± 0.79 ± 0.04 63± 18 1139 ± 380 611 ± 213 SEM ¹Cumulative dose of flecainide withindividual doses shown in parenthesis. ²Measured at the time ofconversion (±1 min). *This animal had a time to NSR (12 seconds) thatwas 2- to 10-fold faster than in the other dogs. Likewise, in this dog,the LV and venous plasma levels (ng/mL) were 10- to 2.7-fold and 15- and2-fold higher, respectively than that observed in other dogs.

FIGS. 68A-D show a representative ECG demonstrating conversion of AF toNSR by IT flecainide, but not by vehicle.

FIG. 69 summarizes the changes in blood pressure (BP), ventricular rate(VR), and LV dP/dtmax (the maximal rate of rise of LV pressure) uponconversion of AF to NSR following administration of flecainide via IV orIT. Flecainide given IV caused greater effects in BP, VR and LV dP/dtmaxupon conversion of AF to NSR compared with IT administration.

The plasma concentrations of flecainide in the pulmonary artery (PA) andleft ventricular chamber (LV) were dependent on the route of delivery(IT and IV) of flecainide (FIG. 70 ). Following IV infusion, theconcentrations of flecainide in the PA were transiently higher (2.1- to3.5-fold) than those in the LV chamber. Conversely, after ITinstillation of flecainide, its concentrations were transiently higher(1.4- to 3.2-fold) in the LV chamber than in the PA.

The ratios of the plasma concentrations of flecainide between LV and PA(and vice versa PA and LV) for IT were reversed to those for IV delivery(FIG. 71 ).

SUMMARY

LV (left atrium) levels of flecainide achieved following pulmonarydelivery of flecainide were sufficient to rapidly terminate AF.

The plasma concentrations of flecainide when delivered via IT weretransiently higher (˜2.5 fold) in the LV than in the PA. Conversely,following IV infusion, flecainide plasma concentrations were transientlyhigher (˜3.5 fold) in the PA than in the LV. At about 4-10 mins afterthe administration of flecainide (IV or IT), the LV and PAconcentrations were nearly equal.

Direct delivery of flecainide to the left atrium using oral inhalationmay prove to be more efficacious, faster, and safer than either the IVor oral delivery alternatives.

The foregoing embodiments and advantages are merely exemplary and arenot to be construed as limiting the present invention. The descriptionof the present invention is intended to be illustrative, and not tolimit the scope of the claims. Many alternatives, modifications, andvariations will be apparent to those skilled in the art.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the methods of the presentinvention can be carried out with a wide and equivalent range ofconditions, formulations, and other parameters without departing fromthe scope of the invention or any embodiments thereof.

All patents and publications cited herein are hereby fully incorporatedby reference in their entirety. The citation of any publication is forits disclosure prior to the filing date and should not be construed asan admission that such publication is prior art or that the presentinvention is not entitled to antedate such publication by virtue ofprior invention.

1. A method of treating atrial arrhythmia, comprising: administering toa pulmonary vein through pulmonary airways by inhalation an effectiveamount of at least one antiarrhythmic pharmaceutical agent selected fromthe group consisting of class I, class II, class III, and class IVantiarrhythmics, to a subject in need thereof, wherein the effectiveamount of the at least one antiarrhythmic pharmaceutical agent is atotal amount from 0.1 mg to 200 mg and has: i) a T_(max) of from about0.1 to about 30 minutes; ii) a C_(max) of from about 10 ng/mL to about5000 ng/mL; iii) an AUC_(Last) of from about 100 hr*ng/mL to about 10000hr*ng/mL; iv) a distribution t_(1/2) of from about 0.1 to about 15minutes; v) an elimination t_(1/2) of from about 1 hour to about 25hours; vi) a maximum ΔQRS of from about 0.01 msec to about 100 msec; orany combination thereof. 2-40. (canceled)
 41. A method of treating aheart condition, comprising administering a pharmaceutically effectiveamount of an antiarrhythmic pharmaceutical agent via inhalation to apatient in need thereof, wherein T_(max) of the pharmaceuticallyeffective amount of the antiarrhythmic pharmaceutical agent afterinhalation is from about 0.1 minute to about 30 minutes; C_(max) of thepharmaceutically effective amount of the antiarrhythmic pharmaceuticalagent after inhalation is from about 10 ng/mL to about 5000 ng/mL; orAUC_(Last) of the pharmaceutically effective amount of theantiarrhythmic pharmaceutical agent after inhalation is from about 100hr*ng/mL to about 10000 hr*ng/mL. 42-52. (canceled)
 53. A nebulized drugproduct, comprising a pharmaceutically effective amount of anantiarrhythmic pharmaceutical agent, wherein T_(max) of thepharmaceutically effective amount of the antiarrhythmic pharmaceuticalagent after inhalation is from about 0.1 minute to about 30 minutes;C_(max) of the pharmaceutically effective amount of the antiarrhythmicpharmaceutical agent after inhalation is from about 10 ng/mL to about5000 ng/mL; or AUC_(Last) of the pharmaceutically effective amount ofthe antiarrhythmic pharmaceutical agent after inhalation is from about100 hr*ng/mL to about 10000 hr*ng/mL. 54-80. (canceled)